Tertiary-amino - substituted i



United States Patent 2,836,598 Patented May 27, 1958 ice TERTIARY-AMING SUBSTITUTED 1,5-13/11110- CYCLOALKANES AND PREPARATION THEREOF Sydney Archer, Albany, N. Y., assignor to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Application August 24, 1954 Serial No. 451,963

26 Claims. (1. 269-292) This invention relates to cycloalkanes having a 1,5- imino bridge and having a hydrocarbon radical attached to the imino nitrogen and a tertiary-amino-1oWer-alkylene group attached through an atom of an element from the group consisting of nitrogen, oxygen and sulfur to the cycloalkane carbon atom in the 3-position. The 1,5- iminocycloalkanes of my invention are preferably employed in the form of their quaternary ammonium salts, however the invention also comprehends the compounds in their acid-addition salt and free base forms. The hydrocarbon radical attached to the imino nitrogen preferably has from one to about ten carbon atoms, and when said hydrocarbon radical contains a phenyl group, the latter may contain inert substituents such as halo, alkyl or lower-alkoxy groups.

A particular aspect of the invention relates to tertiaryamino-substituted tropanes and granatanines and salts thereof, said tropanes and granatam'nes having the general formula:

l 1 2 CH2- HC Ha wherein Y is a divalent radical selected from the group consisting of NH, N(lower-alkyl), N(lo\ver-a1kanoyl), N(monocarbocyclic aroyl), N(lower-alkylcarbamyl), N- (loWer-alkenylcarbamyl), N(monocarbocyclic arylcarbamyl), N(loWer-alkylthiocarbamyl N(loWer-alkenylthiocarbamyl) and N(monocarbocyclic arylthiocarbamyl) n is an integer from 2 to 6, m is an integer from 1 to 2, R is a member of the group consisting of lower-alkyl, monocarbocyclic aryl-loWer-alkyl, and monocarbocyclic aryl, and N=B is a tertiary-amino group selected from the class consisting of di-lower-aikylamino, l-piperidyl, l-pyrrolidyl, 4-morpholinyl, monocarbocyclic aryl-loweralizylamino, and groups having the structure:

The invention also relates to methods for preparing said new tertiary-amino-substituted tropanes and granatanines.

Another aspect of the invention relates to substituted tropanes and granatanines and their salts, said substituted tropanes and granatanines having the general formula:

wherein Y is a divalent atom selected from the class consisting of O and S, -N=B' is selected from the group 2 consisting of di-loWer-alkylamino, l-piperidyl, l-pyrro' lidyl, 4-morpholinyl, and monocarbocyclic arylloWeralkylarnino, and the remaining groups have the same meanings as given above.

My new compounds possess valuable pharmacological properties and in particular are useful as ganglionic blocking agents. The quaternary ammonium salts are particularly valuable for this purpose, although the free bases and acid-addition salts also possess ganglionic blocking action but larger doses are required than for the quaternary arnmonium salts.

In the above general Formulas I and II, the grouping C H represents a loWer-alkylene radical in which the free valences are on different carbon atoms. In other words, the radicals B=N and Y (or Y) are attached to different carbon atoms of the alkylene bridge. The alkylene bridge c H must perforce contain at least two carbon atoms, and can contain as many as about six carbon atoms. The lower-alkylene radicals are straight or branched and include such radicals as ethylene, CH CH 1,3-propylene, CH CH CH l,2-propylene, CH(CH )CH 1,4-butylene, CH CH CH CI-l 1,5-pentylene, CH CH CH CH CH 1 G-hexylene -CH2CH2CH2CH2CH2CH2- 1,2-dimethylethylene, -CH (CH CH(CH and the like. A preferred subgroup of compounds are those in which n is equal to 2, so that the lower-alkylene radical C H is an ethylene (--CH CH group.

In the above general formulas I and II, the tertiaryamino radical N=B or N=B includes cli-lower-alkylamino, saturated N-heterocyclic groups, such as l-piperidyl, l-pyrrolidyl, 4-morpholinyl, and lower-alkylated derivatives thereof (for example, Z-methyl-l-piperidyl, 3-ethyl-l-pyrrolidyl, 3-methyl-4-morpholinyl, and the like), and lower-alkyl-arylamino groups wherein the aryl group is a monocarbocyclic aryl group. The term loweralkyl includes alkyl radicals containing from one to about six carbon atoms, and in the di-lower-alkylamino radicals the lower-alkyl groups can be the same or different. Thus N=B or N=B, when it represents a di-lower-alkylamino radical, includes such groups as dimethylamino, diethylamino, ethylmethylamino, dipropylamino, dibutylamino, dipentylamino and dihexylamino.

The term monocarbocyclic aryl refers to a radical of the benzene series and includes such groups as phenyl and phenyl substituted by inert substituents such as loweralkyl, lower-alkoxy and halogen. Thus N=B or N=B, When it represents a loWer-alkyl-arylamino group, includes such groups as methylphenylamino, N(CH (C H ethylphenylamino, N(C H (C H methyl-4-chlorophenylamino, N(CII (C H Cl-4); methyl-3-rnethoxyphenylamino, N(CH (C H OCH -3); methyI-Z-methylphenylamino, N(CH (C H CH 2) isopropylphenylamino, N(C H (C H butylphenylamino,

hexylphenylamino, N(C H (C l-I and the like. In the preferred types of loWer-alkyl-arylamino groups, the loWer-alkyl groups have from one to about six carbon atoms, and the aryl group is unsubstituted phenyl or phenyl substituted by from one to three loWer-alkyl, loweralkoxy, or halogen radicals, in which the lower-alkyl and lower-alkoxy radicals have from one to about six carbon atoms, and halogen is selected from fluorine, chlorine, bromine and iodine. The term lower-alkoxy is also intended to include the methylenedioxy group, -OCH O-, which, although divalent, can be readily classed with the monovalent alkoxy groups on the basis of its chemical carbon atoms and can be straight or branched.

properties. If more than one substituent is present in the phenyl ring'they can be the same or different n In compounds of FormularI, N=B can also represent a radical of Formula A. The preferred types of compounds Where N=B has Formula A aresymmetrical'com:

pounds in which the moiety A is the same as the corresponding portion in Formula I.

In the above general Formula I, Y represents NH,

N(lower-all .yl) or N(acyl).' When Y is ,hKlower-alkyl), the lower-alkyl groups contain from one to about six I The assaeos N(acyl) groups are amido groups derived from carboxylic acids,'preferably lower-alkanoic acids, monocyclic aromatic carboxylic acids, and carbamic and thincarbamic acids of the type RNHCOOH and R'NHCSGH,

Where R is loWer-alkenyl, low'er-alkyl or mo'nocarbol carbamyl and the like; loWer-alkenylcarbamyl, for example, vinylcarbamyl, allylcarbamyl, 3-butenylcarbamyl The loWer-alkyl and lower-allrenyl groups and the like; monocarbocyclic arylcarbamyl, for example,

phenylcarbamyl, p-tolylcarbamyl, p-chlorophenylcarbamyl, m-methoxyphenylcarbamyl, 3,4-methylenedioxyphenylcarbamyl' and the like; loWer-alkylthiocarbamyl, for example, methylthiocarbamyl, ethylthiocarbamyl, propylthiocarbamyl, isopropylthiocarbamyl, butylthiocarbamyl, pentylthiocarbamyl, hexylthiocarbamyl and the like; lower-alkenylthiocarbamyl, for example, vinylthiocarbamyl, allylthiocarbamyl, 3-butenylthiocarbamyl and the likeyand monocarbocyclic arylthiocarbamyhfor example, phenylthiocarbamyl, p-tolylthiocarbamyl, p-chlorophenylthiocarbamyl, 3,4-methylenedioxyphenylthiocarbamyl and the like. V i

In the above general Formulas I and II, R represents a lower-alkyl, aralkyl or monocarbocyclic aryl' group. The lower-alky l groups can be straighter branched and contain from one to about six carbon atoms. The aralkyl' groups are monocarbocyclic aryl-loWer-alkyl groups in which themonocarbocyclic aryl groups are the same type as described above. groupsas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, hexyl, benzyl, 2-phenylethyl, 3- phenylpropyl, p-chlorobenzyl, m-methoxybenzyl, p-methylbenzyl, phenyl, o-bromophenyl, p-ethoxyphenyl, p-tolyl and the likev 7 Referring to the above general Formulas I and II, the compounds'where m. is l belong to the tropane series Whereas the compounds. where m is 2 belong to the granatanine series. In these compounds there isa possibility of stereoisomerism depending upon Whether the side chain, Y-C,,I'I =13 (or --Y'C, H :13) is on the same side or the opposite side of the molecule as the substituent R. In the tropane series these stereoisomers are known as tropanes and pseudotropanes, respectively. r

a The 1,5-iniinocycloalkanes of the invention wherein the tertiary-amino-lower-alkylene group is attached by NH to theft-position are prepared'by condensing a 1,59

iminocycloalkan-3-one having a hydrocarbon radical at tached to the imino nitrogen with a tertiary-amino-lower' alkylamine," and reducing the resulting imine by catalytic hydrogenation or by chemical means, for example with sodium in the presence of a loWer-alhanol.

The compounds'of Formula I Where Y is NH can be Accordingly R represents such 7 Q ,-a e A A 7 '4' prepared by condensation of a compound having the formula III-12 =0 Queen-r H2 III a with a tertiary-aminoalkylamine, .H NC I-I N=B, under catalytic hydrogenation conditions. The condensa? ,tion and reduction take place: at room' temperaturqalthough heat may be applied if desired. It is convenient to employ a liquidorganic reduction medium, such as ethyl alcohol, which is unreactive with the compound III and tertiary-aminoalkylamine and is not subject to catalytic hydrogenation. Exemplaryof the tertiary-aminoalkylamines which can be used are Z-diethylamihoethylamine, (C H NCH CH NH 3-dimethylaminopropyh amine, C H NCH(CH CH NH 5-( 1-pyrrolidyl) pentylamine, Z-PhenylmethyL- aminoethylamine, C 'H (CH )NCH CH NH and the like. i 7 v The compounds of Formula HI are readily prepared by the classic Robinson synthesis, i."e.,condensation of succindialdehyde or 'glutaric dialdehyde with .a primary amine and'an acetone dicarboxylic acid ester, followed by hydrolysis and decarboxylation, according to the following equation: a

COOEI;

7 Hr cum-CHO l' mun 0:0 omono (EH1. COOEt O'OOEt oHz ...cH- n r 7 Hi0 N-R 0:0. nr CO2 our-- 11 OOO'Et The succindialdehyde (111:1) is conveniently prepared in situ by acid treatment of 2,5-diethoxytetrahydrofuran.

The glutaric dialdehyde is conveniently prepared in situ I byheating glutaric dialdehyde dioxime withsodium nitrite in hydrochloric acid. V

The compounds ofFormula I where Y is NH can also be prepared by condensation of a compound of Formula III and H NC,,H ,,N=B'in the presence of a .dehydrating agent, suchas Zinc chloride,-to give an unsaturated intermediate of the structure followed by reduction of the latter either catalytically or chemically, for'example, by means of sodium in the presence of a lower-alkanoh Catalytic hydrogenation gives substantially exclusively one stereoisomer, belonging to or analogous to. the normal tropane series, Sodiumalcohol reduction, however, usually .yields a mixture of stereoisomers. e V

V The compounds :of Formula I where Y is an N(acyl) group are produced by acylation of the compounds where Y .is NH by heating the latter with the appropriate acid, acid anhydride or acid halide. In thecases where the acyl group is a substituted carbamyl or thiocarbamyl radical, the secondary amine is reacted with the appropriate isocyanate or isothiocyanate. A particular advantage 7 i of the compounds Where Y is N(substituted thiocarbamyl) lies in the fact that these particular derivatives'permit ready separation of the stereoisomers produced by the sodium-alcohol reduction of compounds of FormulaIV.

The separation is accomplished by fractional crystallization from an appropriate solvent such as methanol or ethanol. The pure stereoisomers where Y is NH can then be obtained by hydrolysis of the thiocarbamyl derivatives.

The compounds of Formula I where Y is N(loweralkyl) are obtained by reduction of the compounds where Y is N(lower-alkanoyl) with lithium aluminum hydride. The carbonyl group of the amide linkage is converted to a methylene group; thus a formyl group is reduced to a methyl group, an acetyl group to an ethyl group, and so forth.

An alternative method for preparing compounds of Formula I where Y is N(CH comprises heating compounds where Y is NH with formaldehyde and formic acid.

The compounds of Formula I where N=B has the structure A above can be prepared by the methods described above but are more conveniently prepared by condensation of two equivalents of a compound of Formula III with an alkylenediamine under catalytic hydrogenation conditions. The compound thus produced, a secondary amine where both Ys are NH, can be acylated or alkylated as described above for converting compounds where Y is NH to compounds where Y is N(acyl) and N(lower-alkyl).

The 1,5-iminocycloalkanes of the invention wherein the tertiary-amino-lower-alkylene group is attached by oxygen or sulfur to the 3-position are prepared by reacting an alkali metal 1,5-imino-3-cycloalkoxide or -alkylmercaptide having a hydrocarbon radical attached to the imino nitrogen with a tertiary-amino-lower-alkyl halide, or by reacting a 1,5-imino-3-cycloalkyl halide having a hydrocarbon radical attached to the imino nitrogen with an alkali metal tertiary-amino-lower-alkoxide or -alkylmercaptide.

The compounds of Formula II where Y is O or S are prepared by reacting compounds having the formulas (OHZ)n CH GH2 N-R OHX CHzCH-OH2 and X'-C,,H ,,-N=B' where one of X and X is halogen, preferably chlorine,

bromine or iodine and the other of X and X is OM or i SM where M is an alkali metal. A preferred method where Y is comprises heating a compound of Formula V (X=OM) with a tertiary-aminoalkyl halide The reaction is carried out by first preparing a suspension of V (X=OM) in an inert organic liquid, such as toluene or Xylene, then adding the tertiary-aminoalkyl halide and heating the mixture. Exemplary of the tertiary-aminoalkyl halides which can be used are 2- diethylaminoethyl chloride, (C H NCH CH Cl; 3-dimethylaminopropyl bromide, (CH NCH CH CH Br; 2- dipropylaminopropyl chloride,

C H NCH CH CH CI 4-( l-pip eridyl butyl bromide,

C5HIONCH2CH2CHQCH2BY 5-(4-morpholinyl)pentyl chloride,

OC H NCH CH CH CH CH Cl 2-phenyhnethylaminoethyl chloride,

C H (CH )NCH CH Cl and the like.

The starting materials of Formula V are readily pre- '6 pared from the amino ketones of Formula 111 by reduction of the carbonyl group to a hydroxyl group and then converting the latter to the alkali metal derivative (X=OM) or replacing the hydroxyl group by halogen (X=halogen) The new tertiary-amino-aliphatic substituted tropanes and granatanines are most conveniently used in the form of water-soluble, non-toxic acid-addition or quaternary ammonium salts. Non-toxic salts are salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side efiects ascribable to the anions; in other words, the latter do not substantially increase the toxicity inherent in the cations. Appropriate acid-addition salts are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid and phosphoric acid; and organic acids such as acetic acid, citric acid, lactic acid, and tartaric acid. The quaternary ammonium salts are obtained by the addition of alkyl, alkenyl or aralkyl esters of inorganic acids or organic sulfonic acids to the free base form of the compounds. The alkyl, alkenyl or aralkyl esters so used include such compounds as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, allyl chloride, allyl bromide, methyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, benzyl chloride, benzyl bromide, and substituted benzyl halides, such as p-chlorobenzyl chloride, p-nitrobenzyl chloride, o-chlorobenzyl chloride, p-methoxybenzyl chloride, p-methylsulfonylbenzyl bromide, and the like.

The acid-addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution. The number of equivalents of acid which enter into salt formation depends upon the amount of acid present and the number of amino groups present in the free base. If an excess of acid is used, the number of equivalents of acid entering into salt formation Will be equal to the number of basic nitrogens present in the free base.

The quaternary ammonium salts are prepared by mixing the free base and the alkyl, alkenyl or aralkyl esters in an organic solvent. Heating may be used to facilitate the reaction, although salt formation usually takes place readily at room temperature. The quaternary ammonium salt separates directly or can be obtained by concentration of the solution. The number of equivalents of alkyl halide or other ester entering into salt formation depends upon the amount of ester present relative to the amount of free base, and on the number of tertiaryamino groups present in the free base. The number of tertiary-amino groups present in the free base may vary from two, where Y (or Y) is O, S or NH, to four, where Y is N(lower-alkyl) and N=B has Formula A. If an excess of alkyl halide or other ester is used, some or all of the tertiary-amino groups present in the free base may be quaternized, depending upon reaction conditions such as time and temperature. In compounds of Formula I where Y is NH, N(acyl) or N(lower-alkyl) and where N l3 is dialkylamino, piperidyl, pyrrolidyl, morpholinyl or phenyl-lower-alkylamino, bis-quaternary salts are most often produced, probably involving the nitrogen atoms of the nucleus and N=B. In some cases, however, where Y is N(loweralkyl) tris-quaternary salts are obtained, and mixtures of salts having different degrees of quaternization are sometimes produced.

The quaternary ammonium salts of my invention can be represented by the formula Z.(RX"),,', wherein Z stands for an amine of Formulas I or II, R stands for a hydrocarbon radical, X" stands for an anion, and n is an integer from 1 to 4 depending upon the number of quaternizable centers in the under" which the 'quaternizatiofi reaction takes place:

Preferred types of the hydrocarbon group, R" are those i having immune to about te'n'carbon'atomsjselected from to form the'corr'esp'o'fidi'ng quaternary ammonium hydroxide. Thelatter can then be'neutralized with any desired acid, weak or strong, to producea new quaternary ammonium salt in which tlfe'ariidii is different from that of the original uaternary salt. In this wavquaternary ammonium salts in whichtheariiori X" is derived fror'n'.

a weak acid c'aii'be' obtained.

The follcwingexarn les' will"furtherillustrate the invention. V

- E am I V 3 (2 dierhylziminvethylamino)tropzme [1; Y=NH, 11:2, m=l,'R =CH N:l?"-:N'(C I-I) A mixture of 30 g. of13 tropanoney 24g. of Qadiethylaminoethylamine, .12 got platinum oxide catalyst and 50 ml. of ethyl alcohol was shakenin'a hydrogen'atmosphere at a pressure of 50. lbs. per sq. iHCllIl After two and one-half hours one mole of hydrogen had'been'taken up, the reaction mixture was filtered, and the filtrate was concentrated and distilled, giving 33.2 g. of 3-(2-die thylaminoethylamino)tropane, B. 'P. Ill-115 C. (0.5 mm.).

Analysis-Calm. N, 17.10.

' A portion of the base was convertedto the picrate by addition o f'an ethanol solution of the base to an ethanol solution or picric acid. Thepicrate which separted was collected by filtration and recrystallized from aqueous ethanol, givinga sainple with the M.- P.' 163.5-166'C.

. Example 2 3-(Z-diethylaminoethyl)aminotropane trihydroch loride monohydrata-An excess of. alcoholic hydrogen chloride was added to a solution of 3-(2-diethylaminoethyl)aminotropane in ethanol. The ,crysta-llineproduct which separated was recrystallized first from 95% ethanol and then from methanol, giving 3-(2-diethylarninoethyl)aminotropane trihydrochloridemonohydrate, M.-P. 267-271 C.

A talysLn Calcd. for C H N 3HCLH O: N, 11.46; Cl, 29.00; C, 45.83; H, 9.34.1 Found: N,-1l.94; Cl, 28.85;

7 Example! 3 -[(2 diethylamirioethyl)amino]tropane bismethobromide-An excess of methyl bromide gas (7.0 g;) was passed into 'alsolution of 5.0 gcof 3-[(diethylamino-;

for C H N z N, 17.55. Foundi e Z and the conditions 7 ethy 1)aminol tropane in 25 cc. of methanol over'a period ot'fifteenminutes'with external cooling. The crystalline product? which separated was collected by filtration and mm.)twas collected, giving'42.'5 g. 0ff3-'[(2-d iethylamir o= ethyDarniri'olttOpane bi'sm'eth'obr'omide; 289-2905 C.(dec.). p J Analysisr' Calcti. for C H Br N N, 9.78; Br. 37.2. Poundt N', 9.74; Br; 3710; V

3 2" diethylaminoethyl)methylaminoltrbpahe [15" Y=N(CH3), n=2, m=1, R=CH3,

to solid carbon dioxide temperature and 54 cc. of10'0 formic acid wa's added, followed by 24.6- cc. of 36%* aqueous formaldehyde solution'. The mixture' w'as heated on a steambath for sixteen hours, cooled, made'basic with 35% sodium hydroxide, and the-product-was-extracted with ether, dried over potassium hydroxide'and distilled. The fraction boiling at i201'23 C. (0.8 10 mm.) wascollect'ed, giving 42.5 g. of.3-[-dietliylaminoethyD'me'thylamino]tropane, 'n =1.4871.

' Example'6 3 [(2 diethylarhinoethyl)methylamino]tropaiie tri-" zydr0br0niia'e.A solution -of g. of 3-[(2 dietliyl amindethyDmethylamino]tropane in 250 cc. of absoluteethanol was treated with an excess of alcoholic hydroger'i'.

The crystalline material (34.43.) whieh se'p-f bromide. arated was collected by filtration, recrystallized from methanol and dried for two hours at 100 C. (0'.1 nrm.-);

giving 3-[ (Z-diethylamiribethyl)methyl'amino] tropan'e 'tfihydrobiomide, M. P. above C.

Analysis.-Calcd. for C H N 3HBr: 6. 91; Br, 48.3. FoundrC, 35-.88; H,'7.09; Br, 47.9.

Example 7 p 3 [(2 --diethylaminoethyl)methylamino] tropanebis-i .n'1ethiodide.A 10 g. sample of the trihydrobromide salt'i of 3-[(Z-diethylaminoethyl)methylamino]tropane, :pre-

pared as described'above in Example 6, was converted to Example 8 3 [(2 diethylaminoethyl)mcrhylaminaltropane bis. meth0br0mide.Excess methyl bromide was added to 'a solution of 5.0 g. of 3-[(Z-diethylaminoethyl)methylaminoltropane in 50 cc. of acetonitrile at 0 ,C. The solution was warmed to 30 C., then cooled and kept atr The crystalline-ma; terial which separated was collected by filtration, washed room temperature for three hours.

with acetone, recrystallized from isopropyl alcohol, and dried at 70 C., giving 4.4 g. of 3-[(2-diethylaminoethyl)- methylaminoltropane bismethobromide, M. P. 245-247 C. (dec.).

Analysis.Calcd. for C H N Br N, 9.48 at; 56.1;

Found: N, 9.15; Br, 35.4. V

Example 9 3 [(2 diethylaminbe thyl )methylamino] lropane bisethi0dide.-A solution of 2.5 g; of 3"-[(2 -diethylaminoethyl)methylaminoltropane (Example 5), and 2 'rnl; of ethyl iodide in 5 ml. of absolute ethanol was kept at room temperature for fifteen minutes, then warmed to 60 C.

and allowed to stand at roomtemperaturefor about" fif teen hours. The crystalline product (3.3 g.) was collected by filtration, recrystallized twice frommethanol-- and driedat 55 6., giving 1.17 g. of--3-[ (2-diethy1amino- 2 5)21 v 3-(Z-diethylaminoethyIaminO)tropane (59g) was cooled r 9 ethy1)methylaminoltropane bisethiodide, M. P. 237- 238 C.

Analysis.-Calcd. for C f l' I N N, 7.45; I, 44.98.

Found: N, 7.47; I, 45.30.

Example 10 Example 11 3 [(Z-dimethylaminoethyl)methylamino]tropane [1; Y=N(CH n=2, m=1, R=CH N=B=N(CH 3-(2 dimethylaminoethylamino)tropane (31.6 g., 0.15 mole), prepared as described in Example 10, was cooled to -80 C. by means of a Dry Ice-acetone bath, and then 39 ml. of 100% formic acid was added portionwise followed by 15 ml. of 36% formaldehyde. The mixture was allowed to warm to room temperature and then heated on a steam bath for sixteen hours. The reaction mixture was then cooled, poured into an excess of concentrated potassium carbonate solution, and the product was extracted with ether. The ether extracts were dried over anhydrous calcium sulfate and concentrated, and the residue was distilled, giving 21 g. of 3-[ (Z-dimethylaminoethyl)methylamino]tropane, B. P. 104107 C. (1.2 mm.). n =1.49009.

Example 12 3 [(Z-dimethylaminoethyl)methylarnino] tropane bismethiodide was prepared from a solution of 4.50 g. of 3 [(2 dimethylaminoethyl)methylamino]tropane (Example 11) and 6.25 g. of methyl iodide in 25 ml. of ethanol. The crystalline product which separated was recrystallized from methanol and dried for one-half hour at 100 C. giving 7.0 g. of 3-[(2-dimethylaminoethyl)- methylaininoltropane bismethiodide, M. P. 238241 C. (dec.)

Analysis.-Calcd. for C15H34I2N3 I, 49.8, N, Found: 1, 49.9, N, 8.20.

Example 13 3 [3 (1-piperidyl)propylamino]tropane [I; Y=NH, n=3, m=1, R=CH N=B=NC H was prepared from 46 g. of 3-tropanone and 42.7 g. of 3-(1-piperidyl)propylamine according to the manipulative procedure described in Example 1. There was thus obtained 65.6 g. of 3-[3-(1-piperidyl)propylamino]tropane,B. P. 141-150 C. (0.5 mm.).

Analysis.Calcd. for C H N N, 15.83. Found: N, 15.46.

Example 14 3 {[3 (1 piperidyDpropyl] methylamino tropane} [Y=N(CH n=3, m=1, R=CH N=B=NC H was prepared from 32.8 g. of 3-[3-(l-piperidy1) propylaminoltropane (Example 13), 32 ml. of formic acid and 12.3 ml. of 36% formaldehyde according to the manipulative procedure described in Example 11. There was thus obtained 27.4 g. of 3 {[3 (l piperidyl)propyl]methylamino}tro'pane, B. P. l4l-148 C. (0.2 mm.),

Analysis.Calcd. for C H N C, 73.06; H, 11.90; N, 15.04. Found: C, 72.89; H, 12.15; N, 14.88.

Example 15 3 {[3 (1 piperidyDpropyllmethylaminolltropane bisethiodide was prepared from a solution of 4.8 g. of 3 [3 1-piperidy1)propy1]methylamino}tropane (Example 14) and 5.78 g. of ethyl iodide in 50 ml. of ethanol. The crystalline product which separatedwas recrystallized three times from ethanol and dried at 0., giving 4.2 g. of 3 {[3 (1 piperidyl)propyl]methylamino}tropane bisethiodide, M. P. 222-233" C.

Analysis.Calcd. for C H I N I, 42.92; N, 7.11. Found: I, 44.00; N, 6.84.

Example 16 3 {[3 (1 piperidyl)propyl]methylamino}tropane trismethiodide was prepared from a solution of 4.8 g. of 3 {[3 (1 piperidyl)propyl]methylamin0}tropane (Example 14) and 5.31 g. of methyl iodide in 50 ml. of absolute ethanol. The crystalline product which separated was recrystallized twice from methanol, giving 2.2 g. of 3 {[3 (1 piperidyl)propyl]methylamino} tropane trismethiodide, M. P. 207-214 C.

Analysis.Calcd. for C H I N I, 53.99; N, 5.96. Found: I, 53.2; N, 5.70.

Example 17 3 [2 (1 piperidyl) ethylamino] tropane [1; Y==NH, n=2, m=1, R=CH N=E=NC H was prepared from 46 g. of 3-tropanone and 38.5 g. of 2-(1-piperidyl)ethylamine according to the manipulative procedure described in Example 1. There was thus obtained 65 g. of 3-[2- (l-piperidyl)ethylaminoltropane, B. P. 132-133 C. (0.5 mm.).

Analysis.Calcd. for C H N N, 16.71. Found: N, 16.16.

Example 18 3 [2 (1 piperidyDethylamino] tropane trihydrochloride.A solution of 3-[2-(1-piperidyl)ethylamino]- tropane in ethanol was treated with an excess of ethanolic hydrogen chloride, and the product which separated was recrystallized twice from ethanol, giving 3-[2-(l-piperidyl)ethylamino]tropane trihydrochloride, M. P. 275- 277 C.

Example 19 3 [2 (l piperidyl)ethylamino]tropane bismethiodide-A solution of 3 g. of 3-[2-(1-piperidy1)ethylaminoltropane in 10 ml. of ethanol was treated with 3 ml. of methyl iodide. The crystalline product which separated was collected by filtration and recrystallized from ethanol, giving 5.0 g. of 3-[2-(l-piperidyl)ethylaminolfl'opane bismethiodide, M. P. 293 C. (dec.).

Analysis.Calcd. for C17H35I2N3: N, I, Found: N, 7.75; I, 47.2.

Example 20 3 {[2 (1 piperidyl)ethyl]methylamino}tropane [1; Y=N(CH n=2, m=1, R=CH N=B=NC H l was prepared from 32.5 g. of 3-[2-(1-piperidyl)ethylaminoltropane (Example 17), 33.5 ml. of formic acid' and 12.9 ml. of 36% formaldehyde according to the mainpulative procedure described in Example 11. There was thus obtained 26.9 g. of 3-{[2-(1-piperidyl)ethyl]- methylamino}tropane, B. P. 118.5-126 C. (0.07 mm.).

Analysis.Calcd. for C H N C, 72.40; H, 11.77; N, 15.83. Found: C, 72.26; H, 11.89; N, 15.64.

Example 21 Example 22 3-{ [2 (1 piperidyl)ethyllmethylamino}tropane bismethlodide was prepared from a solution of 4.5 g. of

.Found: N, 7.20; I, 43.2.

Found: N, 7.60;

amen s.

3-{ [2!( l-piperidyl) -ethy1]methylamino}tropa.ne (Exam-.7

ple 20) and 5.31 g. of methyl iodide in' 45 ml. of anhydrous ethanol; arated was recrystallized. twice from .methanoL'during which process some material insoluble in the hot methanol was removed by filtration, giving2i7'g: of3-{[2-(*1piper idyl)ethyl]methylamino}tropane bismethiodide, M. P-

Example 23 3{ [2-( lpiperidyl) ethyl]methyl amino}tropane bisethiodide was preparedifroma solution of-4.5 g. of3{ ['2-(1- ethyl iodide in 5 ml. of ethanol- The. product which separated was recrystallized from ethanol, giving 2.5 g.

. of 3{[2-(1-piperidyl)ethyl]-methylamino}tropane bisethiodide, M. P. 215-219 C.

Analysis.-Calcd. fOrC I-I NJ L N, 7 ,28; I, 44.0.

' Example? 24 46g. of 3-tropanone-and385 g. of 3- (l'-pyrrolidyl)pro pylamine according to the manipulative procedure described in Example 1. There Wasthus obtained 49.5 g.

of 3-[3-(l-pyrrolidyDpropylamino]tropane, B. P. 1'40- 144 C. (0.05 mm.).

. 7 'Example'25 3-{.[3 (1 pyrrolidyl)propyllmethylamino}tropane H;

The crystalline product which .sep

prepared from 25 g. of 3-[3-(1-pyrrolidyl)propylamine]' tropane (Ex-ample"24), 26 m1. of formic acid and.10- ml. of 36% formaldehyde according to the manipula-' tive procedure described in Example 11. There was thus obtained. 8.9 g. of 3-{[3-(l-pyrrolidyl)-propyl]methylamino}tropane', B. P. 129-131" C. (0.20mi), r1 1503140. v

Analysis-eCalcd for C H N3: C,. 72.40; H, 11;77; N, 15.831 Found: C 71.80; H,.11.48 N,- 15.71..

Ex mple 26 3{ [3 (1 pyrrolidyDpropyl]methylamino}tropane. bis-- methiodide was prepared from 8.6 g. of. 3{[ 3-(l-pyr.-.

'rolidyl)propyl]methylamino}-tropane and 10.1 g. of

methyl iodide in 75 ml. of ethanol. The total crystalline product was leached With-200ml; of hot ethanol and. the

mixture was filtered. The material which crystallized fromthe filtrate was recrystallized from ethanol, giving 5 g. of 3{ 3-( 1-pyrrolidyl)propyl]methylamino}tropane.

bismethiodide,.M. P. 226;-228 C. 7

Analysis.-'-Calcd. .for C H I N g Exa mple 27 3- [2-( l-pyrrolidyl) ethylamino] tropane [I; Y=NH, 22:2, m=1, R'=CH N=B=NC H was prepared from 46 g. of 3-tropanone and- 34.2 g. of 2-(1-pyrrolidyl)ethylamine according to the manipulative procedure described in Example 1.- d (l-pyrrolidyl)ethylaminohropane, B. P. 130-135 -C. (0.5 mm) Example 28 1 V 3 [2 (1' pyrrolidyl) ethylaminoyr'opane bis'methiodide.-.A solution of 3.5 g. of 3-[2 -(lpyrrolidyl)ethyl-' amino]-tropane in 50 cc. of ethanol was treated with 4 cc. of methyl iodide. The crystalline material which sepa-- rated was. collected by filtration and recrystallized from d methanol, giving 4.2 g. of 3-[2-(l-pyrrolidyl)ethylarnino} tropane bismethiodide, M. P. 290-293 C. (dec.).

Analysis.Calcd. for C13H33I2N3I N, 5.07; I, 48.7. Found: N, 7.80; I, 48.6.

There was thus obtained 31 .6 g. of 3-[2- v Example 29 3 {[2 (1 pyrrolidyl)ethyl]methylamino}tropane ['I; Y'='N(CH3), "=2. m=.1'. c 3. N'= 4 ;;1. prepared from 23.7 g. of 3-[2-(l-pyrrolidyDethylamino] tropane (Example 17) according tonthe manipulative proseparated was recrystallized'frorn methanol, giving 4.1 g. 01 3{ l2-(l-pyrrolidyl)ethyllmethylaminohrdpane his- 7 methiodide, M. P. 205-2209-(3. W

AnalysisCacld. for c an i N l 'N, 7.85; 1,415.5 Found: N, 7.74; I, 48.00.

' Erample 31 V 3-[4-(l-pyrrolidyDbntylamino] tropane [1; =NH, n=4, m=1, R=CH N=B=NC H J was prepared from 27.2 g.-of 3-tropanone and 25.2 g. of 4-(l-.pyrr0lidyl).-. butylamine according to themanipulative procedure tiescribed in Example 1. There was thus obtained-35.l g. V of 3-[4=(hpyrrolidyDbutylamino]-tropane, B. P. 142- 148 C. (0.3 mm), n =1.5038-41.

Example 32 3-{ [4'- (1 pyrrolidyl)butyl]methylamino}tropane [I;., Y=N(CH n=4, m=1, R CH N=B=NC H 1wa prepared from 30.8 g. of'3-[4-(1-pyrrolidyl)butylamino] tropane (Example 31), 30 ml. of formic acid and 11.6 ml. of 36% formaldehyde according'to the manipulative pro... cedure described inExample 11. There was thus obtained. 14.3 g. 'of' 3-{[4-(l-pyrrolidyl)butyl]metl1ylamino}tro= pane, B. P. 138140 C. (0.2 mm.), n =1-.502 9.

Example 33 V V .3-[2 (4-morpholinyl)ethylaminoltropane El; .Y jNH; Q 11:2, m='1', R=CH NB=NC4H Olwas prep 'd" from 42 g. of 3-tropanone, 42 g. of .4-(2rarninoethyl') morpholine and 0.6 g. of platinum oxidecatalysti accord-.. ing to the manipulative procedure given above in Example I. There was thus obtained 51 g. of 3-[2-(4-morpho- IinYDethyIaminQltropane, B. PQ133-135". C. (0.4 man), 1

n =1.5066. (v V a i V d 7 Example 34 T j d 3 [2; (4,morpholinyl ethylaminol tropqne IFihydI'QQHLO-i ride.-,A solution'of 5.0:g. of 3-[2-(4-morpholinyl)ethyl-,

aminoltropane in 50 cc. of ethanol. was treated with an excess of ethanolic hydrogen chloride. The product: which separated was collected by filtration and recrystallized from methanol, giving 5.5 g. of 3-[2-(4-morpholinY1).

ethylaminoltropane trihydrochloride, M; P. 245-249.?

c. (dec.). H 7

fr Example 35 "3"- [2 4 (4-morph0linyl)cthylaminoltropane bism'ethiodide.-A solution of 7.0 g. of 3-[2-(4-morpho1inyl)ethylaminoltropanedn .150 cc. of ethanol was treated with6 cc. of methyl iodide; The icrystalline; material which I separated was" collected by filtration and recrystallized" first from dilute ethanol and then from water, giving'3i8 g. of 3-[2-(4-morpholinyl)ethylaminoltropane bismethiodide, M. P. 2645-265 C. (dec.)

j 3-{[2.- (4- morpholiny )ethyll'methylamjnohropan'ai n;

prepared .from 365; g.. of 3.-[2- (4-morpholi nyl)'e thy 1- aminoltropane, 37.6'cc. of' formic acid andf14.5' cc. of,

36% formaldehyde solution according to the manipulative procedure described above in Example 11. There was thus obtained 29.3 g. of 3-{[2-(4-morpho1inyl)- ethyl]methylamino}tropane, B. P. 124-l30 C. (0.1 mm.), ;1 =1.5079-83.

Example '7 3-{12-(4 morpholinyl) ethyl] methylamino}tropane trihydrobromide.A solution of 3 {[2 (4-morpholinyl) ethyllmethylamino}tropane in ethanol was treated with an excess of ethanolic hydrogen bromide. The product which separated was collected by filtration and recrystallized from methanol, giving 3-{[2-(4-morpholinyl)ethyl]- methylamino}tropane trihydrobromide, M. P. 252254 C. (dec.).

Analysis.Calcd. for C H N O3HBr: C, 35.31; H, 6.32; Br, 47.0. Found: C, 35.31; H, 6.83; Br, 46.8.

Example 38 Example 39 3-(3-dimethylaminopropylamino)tropane [1; Y=NH, n=3, m=1, R=CH N=B=N(CI-l was prepared from 46 g. of 3-tropanone and 30.7 g. of 3-dimethylaminopropylamine according to the manipulative procedure described in Example 1. The product was distilled at 108-119 C. (0.1 mm.) and then redistilled, giving 38.0 g. of 3-(3-dimethylaminopropylamino)tropane, B. P. 112414" c. 1.7 mm.), n =l.4990.

The picrate was prepared by dropwise addition of an ethanol solution of the free base to a solution of picric acid in ethanol. The picrate which separated was re crystallized twice from dimethylformamide, giving a sample, M. P. about 230 C. Analysis showed it to be a tripicrate.

Analysis.-Calcd. for c n u o N(NO2), 13.81. 4

Found: N(N0 13.79.

Example 40 3- 3-dimethylaminopropyl) methylamino] tropane [1; Y=N(CH 12:3, m=1, R=CH N=B=N(CH was prepared from 30 g. of 3-(3-dimethylaminopropylamino)tropane (Example 39), 30 m1. of formic acid and 14.1 ml. of 37% formaldehyde according to the manipulative procedure described in Example 11. There was thus obtained 24.8 g. of 3-[(3-dimethylaminopropyl) methylaminoltropane, B. P. 106112 C. (0.5 mm.), n =1.4885-8.

The picrate, prepared as described for the compound of Example 21, had the M. P. 231 C. (dec.).

Example 41 3-(3-diethylaminopropylamino)tropane [1; Y=NH, n=3, m=1, R=CH N=B=N(C H was prepared from 46 g. of 3-tropanone and 39.1 g. of 3-diethylaminoproylamine according to the manipulative procedure described in Example 1. There was thus obtained 52.5 g. of 3-(3-diethylaminopropylamino)tropane, B. P. 120-125 C. (0.1 mm.), n =1.4862. V

The picrate, prepared as described for the compound of Example 21, had the M. P. 212 C. (dec.).

Example 42 3 [(3 diethylaminopropyl)methylaminoltropane [1; Y=N(CH 71 3, m=1, R=CH N:'B=N(C H was prepared fiom 49.0 g. of 3-(3-diethylaminopropyl- 14 amino)tropane (Example 41), 50 ml. of formic acid and 19.2 ml. of 37% formaldehyde according to the manipulative procedure described in Example 11. The product was distilled at 128148 C. (0.8 mm.) and then redistilled, giving 31.4 g. of 3-[(3-diethylaminopropyl)- methylaminoltropane, B. P. 120-123 C. (0.1 mm.), 11 1.4870.

Analysis.--Calcd. for C I-1 N C, 71.85; H, 12.44; N, 15.71. Found: C, 71.81; H, 12.47; N, 15.59.

Example 43 3-[(3 diethylaminopropyl)methylamino]tropane bismethiodide was prepared from a solution of 2.67 g. of

3 [(3 diethylaminopropyl)methylamino]tropane (Ex-.

ample 42) and 1.25 ml. of methyl iodide in ml. of ethanol. There separated from solution 3.2 g. of 3-[(3- diethylaminopropyl)methylamino1tropane bismethiodide, M. P. ZZZ-227 C.

Analysis.-Calcd. for C H I N I, 46.2. Found: I, 46.6.

Example 44 N,N'-bis(3tropanyl) ethylenediamine [1; Y=NH, 21:2, m=l, R=CH N= B=A].-A mixture of 40 g. of 3- tropanone, 8.4 g. of ethylenediamine, 1.5 g. of platinum oxide catalyst and 150 ml. of ethanol was shaken in a hydrogen atmosphere at a pressure of 49 lbs. per sq. inch. After six hours 1 mole of hydrogen had been taken up, the reaction mixture was filtered, and the filtrate was concentrated and distilled, giving N,N'-bis(3-tropanyl)ethylenediamine, B. P. 178-181 C. (0.6 mm.).

Example 45 N,N'-bis(3-tropanyl) N,N' dimethylethylenediamine [1; Y=N(CH 11:2, m=1, R=CH N=B=Al was prepared from 27 g. of N,N-bis-(3-tropanyl) ethylenediamine (Example 44), 18.3 ml. of 36% formaldehyde and 40 ml. of formic acid according to the manipulative procedure described in Example 11. There was thus obtained 19.3 g. of N,N'-bis(3-tropanyl)-N,N-dimethyl ethylenediamine, B. P. 192200 C. (1.5 mm.), which solidified upon standing.

Example 46 N,N'-bis(3-tropanyl) N,N dimethylethylenediamine bismethiodide was prepared from a solution of 3.30 g. of N,N-bis(3 tropanyl) N,N-dimethylethylenediamine (Exmple 45) and 3.02 g. of methyl iodide in 20 ml. of absolute ethanol. The crystalline product which separated was recrystallized twice from methanol and dried at 100 C., giving 2.0 g. of N,N'-bis(3-tropanyl)-N,N- dimethylethylenediamine bismethiodide, "V1. P. 273-274 C. (dec.).

Analysls.-Calcd. for C H I N N, 9.06; I, 41.04. Found: N, 8.84; I, 41.03.

Example 47 3-(2-dimethylaminoethoxy)tropane [11; Y'=O, n 2, m=1, R=CH N=B'=CH ].A solution of 60 g. of tropine in 50 ml. of toluene was added to a stirred suspension of 9.2 g. of sodium in 100 ml. of toluene, and the mixture was refluxed for four hours. A solution of 42.8 g. of Z-dimethylaminoethyl chloride in 50 cc. of toluene was then added, and the reaction mixture was refluxed for three hours. After cooling, methanol and water were carefully added, the organic layer was separated and concentrated, and the residue distilled at 86-91 C. (1.0 mm.), and then redistilled, giving 17.3 g. of 3-(Z-dimethylaminoethoxy)tropane, B. P. 85.5 C. (0.9 mm.), n =1.4836.

Example 48 3-(2-dimethylamin0ethoxy)rropane bisperchl0rate.-

A solution of 2.12 g. of 3-(2-dimethylaminoethoxy)tropane (Example 47) in 25 ml. of acetic acid was added to a solution of 3.0 g. of 72% perchloric acid in 25 ml.

of acetic acid. .A heavy precipitate formed which. was Collected by filtration, recrystallized from 90% aqueous acetic acid and dried at 75 C., giving 2.0 g. of 3-(2-di- Example 49. V

3-(2-dimethylaminoethoxy) tropane bismethiodide was prepared from a solutionof 2.12 g. of 3-(2-dimethylaminoethoxy)tropane (Example 47) and 2.0 ml. of methyl iodide in 15 ml. of ethanol. The crystalline product which separated was recrystallized twice from methanol and'dried for hour hours at 100 0., giving 1.4 g. of "3-(2- dimethylaminoethoxy)tropane bismethiodide, M. P. 314- 315 C. (dec.)-.- 7 V -Arzalysis.-Calcd. for C H l N- o: Found: 1, 51.17; N, 5.59.

i V Example 50 3-(2-dimethylaminoethoxy)tropane bisethiodide was prepared from a solutionof 2.12 g. of 3-(2-dimethyl aminoethoxy)tropane (Example 47) and ml, of ethyl iodide in 10 ml. of ethanol. The crystallinepr oduct which separated Was'dried at 1'00. C. for forty-eight hours, giving 2.0 g. of 3-(2-dirnethylaminoethoxy)tropane biscthiodide, M. P. 269l275 C. i V

Analysis.Calcd.. for c n n u o; I, 49.36. Found:

' J Example 5 1 I h V 7 3-(2-diethylaminoethoxy)tropane III; Y=O, 41:2, in:l, R=- -CH N=B'=N(C 1 -I was prepared from 60 g. of tropine, 9.2 g. of sodium and 54 g.; of 2-diethylaminoethyl chloride according to the manipulative procedure described in Example'47. There was thus obtained 38.3 g.'of 3-(2-diethylaminoethoxy)tropane, B. P. 101 .C. (007mm), n =l.4758. r

Example 52 3-(2-diethylaminoethoxy)tropane bismethiodide. was prepared from a solution of 7.2 g. of 3-(2-diethylaminoethoxy)tropane (Example 51) and 5 ml. of methyl iodide in ml. of ethanol- The crystalline product which separated was recrystallized twice from methanol and Example 53 3-(2-diethylaminoethoxy)tropane bisallobromide can be prepared from a solution of 3(2-diethylaminoethoxy)- tropane (Example 51) and an excess of allyl bromide in ethanol. 7

Example 54 3-(2-diethylaminoethoxy)tropane bisbenzochloride' can '15 Example .56.

. 3: [2 -(1 piperidyl ethoxy tropane Q bismethiodide.A

solution. of 55.04 gfof 3-[2-(1-piperidyl)ethoxy]tropane' in,25 ml. of ethanol was treated with 5.69 g. of methyl iodide. The crystalline productfwhichIseparated. was

collected by filtration and recrystallized from ethanol,

giving 7.0 g. of 3-[2-(1-piperidyl)ethoxy]tropane bismethiodide, M. P: above 305 C. Y

Analysis.Calcd. for C H I N O: N, 5.23; I, 47.3; Found: N, 5.31; I, 47.5.- V

Example 57 3-[3-(l-piperidyDpropoxy]tropane ['II; Y=O, n=3,

56.3 g. of tropine,'8.65 g. of sodium and 60.7 g. of 3-(1- piperidyhpropyl chloride according to the manipulative proceduredescribed above in Example 47. There wasthus obtained 61.3 g of 3.-[3-(l-piperidyDpropoxyltropane, B; P. 115 C. (0.1 mm.). 7

Analysis.-Calcd. for C l-1 N 02 N, 10.52. Found:

7 Example 58 3 [3 (J pipridyl) propmgy trapane I bism ethi0dide. A solution of 5 .32 1 g. of 3- [3-( l piperidyl)propoXy] tropane 'in 25 ml. of ethanol was treated with 5.69 g. of methyl iodide. The crystalline material which separated was collected by filtrationand recrystallized twice from ethanol, giving 8.0 g. of' 3-['3-(l-piperidyl)propoxy ]tropane bismethiodide, M. P. above 305 f C.

Analysis.Calcd. for C H3' I N O: I, 46.1; C, 39.28;

'H, 6.59; Found: I, 45.8; C, 38.66; H, 6.81. 5

Example 59 one-half hour to aisuspension of1l2' g. of sodium amide in 100 ml. of dry toluene; and the mixture was refluxed for'six hours. A, solution of 51 g. of 2-(1pyrrolidyl) ethyl chloride in ml. of dry toluene Was' then added dropwise during one hour, and the reaction mixture was refluxed for six hours. After cooling, ethanol andwater were carefully added, the organic layer was separated and concentrated, and the residue was distilled at 113- 123 C. (1.2 mm.) and redistilled, giving 19 got 3-[2- (l-pyrrolidyl)ethoxy]tropane, B. P.'134 C. (2.8 mm.),

' Example 60 dried at 100 C. for twenty-four hours, giving g. of 3-[2-(l-pyrrolidyl).ethoxy]tropane bismethiodide, M. P..

be prepared frorn'a solution or" 3-(Z-tiiethylaminoethoxy)- trooane (Exam le 51) and an excess of benzyl chloride in ethanol.

7 V Exmizple 55 Z r V 3-[2-(l-piperidyDethoxy]tropane ill; Yf=-O,' 11:2, 112:1, R H N=B'= NC H was prepared from 164g. of tropine, 985g. of sodium and 63 g. of 2-(1- piperidyhethyl chloride according to the manipulative procedure described above in; Example 47. There was thus obtained 40g. of 3-[2-(l-piperidyl)ethoxy]tropane, B. P. 106-109 C. (0.07 .mm.). 7 V

, Analysis.-Calcd. for C l-lg N ot N, 11.10. Found:

Analysis.Calcd. for-C H I N O: I, 48.6. Foundi 1,493. a

3-[2-.(1-pyrrolidyl)ettioxy]tropane was found to have a ganglionic blocking activity equal to that of hexamethonium bromide (see Example 3). V

' Example 61 3- (2-diethylaminoethoxy) pseudotrop ane from 49.2-g. of pseudotropin e, 7.6g. of sodium and.44.3 g.

of Z-diethylaminoethyl chloride using the manipulative procedure described inExample 47, except that benzene was used as. the re action mediurn instead of toluene There was thus obtained 3-(2-diethylaminoethoxy)pseudotropane, B. P. 109-112 C. (0.25 mm.), n =1.477 5. This is a stereoisomer of the compound prepared in Example 51. I r

1 Example 62 3-(2-di'ethylarninoethoxy)pseudotropane bismethiodide was prepared from 5.3 g. of 3-(2-diethylaminoethoxy)- pseudotropane (Example 61) and 6.91 g. of methyl iodide in 30 ml. of ethanol. There was thus obtained 6.3 g.

of 3-(2-diethylaminoethoxy)pseudotropane bismethiodide, M. P. 307-308" C. (dec.).

Example 63 3-(3-diethylarninopropoxy)tropane [II; Y'=O, 11:3, m=1, R=CH N=B=N(C H was prepared from 48.7 g. of tropine, 7.46 g. of sodium and 48.5 g. of 3-diethylaminopropyl chloride according to the manipulative procedure described above in Example 47. There was thus obtained 32 g. of 3-(3-diethylaminopropoxy)tropane, B. P. 94-96 C. (0.2 mm.), 7

Analysis.--Calcd. for C H N O: N, 11.01. Found: N, 10.79.

Example 64 3-(3-dietlzylaminopr0poxy)tropane bismethidide.-A solution of 5.1 g. of 3-(3-diethylaminopropoxy)tropane in 25 ml. of ethanol was treated with 5.69 g. of methyl iodide. The crystalline product which separated was collected by filtration and recrystallized from ethanol, giving 6.5 g. of 3-(S-diethylaminopropoxy)tropane bismethiodide, M. P. 300 C. (dec.). p

Analysis.--Calcd. for C H I N O: N, 5.21; I, 47.1.

Found: N, 5.24; I, 46.7.

Example 65 Example 68 3"(Z-diethylaminopropoxy)tropane [11; Y'==O,

c rr 'c'n cmom m=1, R=CH N=B=N(C H can be prepared from tropine, sodium and Z-diethylaminopropyl chloride according to the manipulative procedure described in Example 47.

Example 69 3 (2 phenylmethylaminoethylamino)t r o p a n e [1; Y=NH, 11:2, m=1, R=CH N=B:N(CH )(C H )l was prepared from 50.6 g. of N-methyl-N-phenylethylenediamine and 51.5 g. of 3-tro'panone according to the manipulative procedure described in Example 1. There was thus obtained a product boiling at 157-171 C. (0.1 mm.) (27.2 g.) which was redistilled to give 3-(2- phenylmethylaminoethylamino)tropane, B. P. 167-1'73 C. (0.1 mm). I

Example 70 3-[(2 phenylmethylaminoethyl)methylaminoltropane [1; Y=N(CH n=2, m=1, R=CH N=B=N(CH (C H was prepared from 29.7 g. of 3-(2-phenylmethylanli'no- "etii iami'nomopane (Example 69), 28.1 ml. of formic acid and 10.9 'ml. of 37% formaldehyde according to the manipulative procedure described in Example 11. The product was distilled giving 7.5 g. of 3-[(2-phenylmethylaminoethyl)methylarninoltropane, B. P. l70172 C. (0.3 mm.).

Example 71 3-[ (2 phenylmethylaminoethyl)methylamino]tropane bismethiodide was prepared from a solution of 7.5 g. of 3-[ (Z-phenylmethylaminoethyl)methylaminoltropane (Example 70) and 8.16 g. of methyl iodide in 35 ml. of anhydrous ethanol. The crystalline product which separated was recrystallized from water giving 5.2 g. of 3-[ (2- phenylmethylaminoethyl) methylamino 1 tropane bisrnethiodide, M. P. 264-267 C. (dec.).

Example 72 3-(Z-phenyIethylaminoethylamino)tropane [1; Y= NH, n=2, m=1, R=CH N=B=N(C H (C l-1 was prepared from 51.9 g. of N-ethyl-N-phenylethylenediamine [B. P. 97-99 C. (0.2 mm.), n =1.5625, prepared by condensation of N-(2-bromoethyl)phthalimide and N-ethylaniline] and 485 g. of 3-tropanone according to the manipulative procedure described in Example 1. There was thus obtained 78 g. of 3-(2-phenylethylaminoethylaminofiropane, B. P. l74-177 C. (0.6 mm.).

Example 73 3 (2 phenylethylaminoethylamind)tropane 8 methiodide.A solution of 3 g. of 3-(2-phenylethylethylaminoethylarninohrcpane in 25 cc. of ethanol was treated with 3 cc. of methyl iodide. The crystalline material which separated was collected by filtration and recrystallized first from ethanol and then from methanol, giving 3 (2 phenylethylarninoethylamino)tropane 8 methiodide, M. P. 226-228 C. (dec.). 7

Analysis.-Calcd. for C H lN N, 9.79; I, 29.6. Found: N, 9.75; I, 29.2.

Example 74 3 [(2 phenylethylaminoethyl)methylamino]tropane was prepared from 31.2 g. of 3-(2-phenyethylarninoethylamino)tropane (Example 72), 28.1 ml. of formic acid and 10.9 ml. of 37% formaldehyde according to the manipulative procedure described in Example 11. The product was distilled giving 17.6 g. of 3-[(2-phenylethyl amino.- ethyljm'ethylaminoltropane, B. P. 174178 C. (0.5 mm.),

Example 75 3 [(2 phenylethylaminoethyl)methylaminoltropane bismethiodide was prepared from 15.5 g. of 3-[(2-phenylethylaminoethyl)methylamino] tropane and 16 g. of methyl iodide in 75 ml. of ethanol. The total crystalline product was leached with ethanol and the undissolved portion was recrystallized from water, giving 2 of 3-[(2-phenylethylaminoethyDmethylamino]tropane bismethiodide', M. P. 269-271 C.

Analysis.Calcd. for C H N I N, 7.18; I, 43.4. Found: N, 7.22; I, 43.2.

Example 76 3 (2 phenylethylaminoethyl) m'ethylamino] tropar'ze 8-methiodide. T he ethanol soluble portion from the prepartion of the bismethiodide in Example 75 was concentrated and the residue was recrystallized from ethanol, giving 6.0 g. of 3 [(2 phenylethylaminoethyl)methylatii indltr o'pane S-methiodide, M. P. 235-238" C.-

AnalysisLCalcd. for C H IN N, 9.48; I, 28.6. Found: N, 9.51; I, 28.6.

Example 77 3' [(2 phenylethylaminoethyl)methylaminoltropane bismethobromide was prepared from20 g. of 3,-[(2-phenylethylaminoethyl)methylamino]tropane and an excess (20 g.) ofmethyl bromide in 80 'ml. of methanoll The product which separated (9.5 g.) was-collected byfiltration and recrystallized from aqueous methanol, giving 3 [(2 phenylethylaminoethyl)methylamino]tropane bismethobromide, M. P. 262262.5 C. (dec.).

Found; N, 8.58; Br, 32.4. e V

' Example 78 3 (2 l phny le thylamz'noetllyl)methylamino] tropanc' aminoethyDmethylamino] tropane in 10 cc. of acetonitrile 'was treated with 3 cc. of ethyl iodide. The crystalline material which separated was collected by filtration and recrystallized from water, giving 3-[(Z-phenylethylarhinoethyl )methylamino]tropane bisethiodide, M. P. 253-254" C. (dec.). i

Analysis.Calcd. for C33H41I2N3I Found: N, 6.83; I, 41.2.

Example 79 i i 1(a) 8 benzylnortropanone.-2,5 diethoxytetrahydrofuran 160 g.) was suspended in 1 0 cc. of water and 0.13

to 25 C., and 202 g. of ethyl acetonedicarboxylate was added followed by 100 cc. of water and benzylamine hydrochloride prepared from 107 g. of benzylamine and 83 cc. of concentrated hydrochloric acid. The reaction mix ture was stirred overnight, treated with 250 cc. of hydrochloric acid, and heated and stirred during which time water was slowly distilled 01f After five and one-half hours 270 cc. of water had been distilled off, the temper- 10 {ethyl acetonedicarboxylate and 27.4 'g. of p-methoxy- -cc. of concentrated hydrochloric acid was added. The f suspension was stirred at 48-50 C. for two hours, cooled ature had risen from 90 to 103 C., and the reaction mix-- ture was then filtered, the filtrate was made basic 'with 250 cc. of sodium hydroxide, 5 00 g. of potassium' carbonate was added and the mixture was extracted three timeswith ether. The ether extracts were dried over anhydrous calcium sulfate, concentrated, and the residue Example 80 i 3 (2 diethylaminoethylamino) bcnzylizo rtropane 'trihydr0chl0rida- -A solution of 4.0 g. of.3'-(2-diethy1- aminoethylamino) 8 benzylnortropane' in 10cc. Ofethanol was treated with an excess of ethanol id. hydrogen chloride; The'crystalline material which separated .was collected by filtration and recrystallized twice fromin'ethanol, giving 3-(Z-diethylaminoethylamino)-8-benzylnortropane trihydrochloride, M. P. 264-266 C. (dec.

v (a) 8-(2,3 dimethoxybenzyDnortropanone'- was. pre- Analysis.-Ca1cd. for C H N 3HCI; Cl, 25.03; N, e

9.89. Found: 01, 24.97; 9.ss. Example '81' 3 (2 diethylaminoethylamifio) 8 'beiizylriortropane bismethi0dide.3 (2" diethylaminoethylamino) 8'- benzylnortropane (obtained by neutralization'of '15 got its hydrochloride salt) was dissolved in 40 ml. of 'ac'et'oni trile and 10 ml. of absolute ethanol, and the solution was treated with 15.0 ml. ofmethyl iodide. The crystalline Found: N, 6.90;-I, 42.20.

, 8-(4-methoxybenzyDnortropane material which separated was collected by filtration and recrystallized from methanol, giving 8.0 g. of 3-(2-diethy1- thylamino) -8-benzylnortropane bismethiodide, 4 M.

Analysis-Calm. for c gn N i N, 7.01; I, 42.35.

Example 82' (a) 8 (4 methoxybenzyDnortropanone was prepared from 32 g, of 3,5-diethoxytetrahdrofuran, 40.5 cc. of

benzylamine acording to the manipulative procedure given above in Example 79, part'a. The product boiling at '162-180 C. (0.1 mm.) was collected'and redistilled, giving 8-(4-methoxybenzyDnortropanone, B.'P. 179-184 C. (0.1 mm), n =1.5538. The latter base was con verted to the hydrochloride salt byadding an excess of '4' N ethanolic hydrogen chloride;- The hydrochloride salt had the M. P. 203-204 C. (dec.) when'recrystaL lized from ethanol. 1 r e (b) 3 (2 diethylaminoethylamino) -.8 {(4 methoxybenzyl)nortropane [1; Y: NH, 11:2, m=1,

-N=B=N(C H was prepared from 8-(4-methoxy benzyDnortropanone (obtained from neutralization of 6.68 g. of its hydrochloride salt), 3.0 g; of Z-diethylaminoethylamineand 0.5 g. of platinum oxide catalyst according to the manipulative procedure given above in Ex-' ample 1.

Example .83

(2 diethylaminoethylamino) 8 (4 metlzaxybenzyl)nortr0pan e trihydr0chl0ride.The crude 3-(2-diethylaminoethylamino) 8 (4 methoxybenzyhnortropane obtained above in ExampleSZ, part 'b, was. dissolved in 25 ml. of ethanol and treated with an excess of ethanolic hydrogen chloride. rated was collected -by filtration and recrystallized from methanol, giving 6.5 g. of 3-(2-diethylaminoethylamino)- 277-278 C. (dec.). V e I Analysis.-Calcd. for C H N O.3HCI: C, 55.44; H, 8.42; N, 9.24. Found: C, 55.63; H, 8.51; N, 9.28.

Example 84 3 (2 diethylaminoethylamino) 8 (4 methoxyben- -zyl) nortropane bismethiodide.3-(2 diethylaminoethyl amino) 8 (4 methoxybenzyDnortropane (obtained by neutralization of 9.0 g.:'of itshydrochloride salt) in 50 'cc. of acetonitrile was treated with 7.5 cc. of methyl iodide. The crystalline material which separated (8.2 g.) was collected by filtration and recrystallized from methanol, giving 3 (2 diethylaminoethylamino) 8- (4-methoxybenzyl)nortropane .bismethiodide, M; P. 229 230C. r

Analysis.-Calcd. for C 3H I N O': N,'6.51; 'I,39.3.

'Found: N, 6.68; 1, 10.0.v

Example 85 .paredfrom 40 g. of'2,idiethoxytetrahydrofuran, 50g.

.of ethyl acetonedicarboxylate and 42 g. of 2,3-dimethoxybenzylamine according to the manipulative procedure vgiven above in Example. 79, part a.. There wasgthus' obtained 28.5 g. of S -(2,3-dimethoxybenzyl)nortropanone, B. P. 17 8199-.C (0.5 mm.),iwhich was converted to its hydrochloride salt, M. P. 201202 :C. (dec.). (b) 3 (2 diethylaminoethylarnino) 8.4 (2,3 dimethoxybenzyDnortropane [1; Y. ?NH; iz=2, m=1,

N=B=N(C H was prepared from szs-dimihexybenzyDnortropanone (obtainedby neutralization of 16.2

g. of hydrochloride salt), 7.0 g. of Z-diethylaminoethyl- The crystalline product which sepatrihydrochloride, M. P.

amine and 1.0 g. of platinum oxide catalyst according to the manipulative procedure described above in Example 1.

Example 86 3 (2 dier'izylaminoezhylumino) 8 (2,3 dimethoxyberzzyl)nrtropane trihydrochlorldex The crude 3-(2-diethylaminoethylanzino) 8 (2,3 dimethoxybenzyl)nortropane, obtained above in Example 85, part b, was reated with an excess of ethanolic hydrogen chloride. The crystalline product which separated was collected by filtration and recrystallized from ethanol, giving 14 g. of 3 (2 diethylaminoethylamino) 8 (2,3 dimethoxybenzyDnortropane trihydrochloride, M. P. 234-237 C.

Analysts-Calm. for C H N O 3HCl: C, 54.55; H, 8.32; Cl, 21.97. Found; C, 54.35; H, 8.03; CI, 21.93.

Example 87 3 (2 dietltylaminoethylamino) 8 (2,3 dimetlloxybenzyl) nortropane bismethi0dz'de.3 (2 diethylaminoethylamino) 8 (2,3 dimethoxybenzyl)nortropane (obtained by neutralization of 7.2 g. of its hydrochloride salt) was dissolved in ml. of acetonitrile and treated with 6 ml. of methyl iodide. The crystalline material which separated (5.8 g.) was collected by filtration and recrystallized first. from ethanol and then from methanol, giving 3 (2 diethylaminoethylamino) 8 (2,3 dimethoxybenzyl)nortropane bismethiodide, M. P. 226-228 C.

Analysis.-Calcd. for C H I N O N, 6.37; I, 38.50. Found: N, 6.49; l, 38.40.

Example 88 (a) 8 (3,4 methylenedioxybenzyDnortropanone was prepared from g. of 2,5 diethoxytetrahydrofuran, g. of ethyl acetonedicarboxylate and 38 g. of 3,4-methylenedioxybenzylarnine according to the manipulative pro cedure described above in Example 79, part a. In this case the hydrochloride salt separated directly from the crude reaction mixture and was collected and recrystallized from water, giving 31 g. of 8-(3,4-methylenedioxybenzyDnortropane trihydrochloride, M. P. 223223.5 C. (dec.).

(12) 3 (2 diethylaminoethylamino) 8 (3,4 methylenedioxybenzyl.)nortropane [1; Y =NH, n=2, m=l,

pared from 8-(3,4-methylenedioxybenzyDnortropane (obtained from 14.8 g. of its hydrochloride salt by treatment with 2.8 g. of potassium hydroxide and extraction), 7.0 g. of Z-diethylarninoethylamine and 1.0 g. of platinum oxide catalyst according to the manipulative procedure described above in Example 1.

Example 89 3 (2 dietlzylami:zoezhylamino) 8 (3,4 methylenedioxybenzyl)noi'tropane trihylZr0chl0ride.The crude 3 (2 diethylaminoethylamino) 8 (3,4 methylenedioxybenzyDnortropane obtained above in Example 88, part b, was treated with an excess of ethanolic hydrogen chloride. There was thus obtained 21.2 g. of 3-(2-diethylaminoethylamino) 8 3,4 methylenedioxybenzyl)nortropane trihydrochloride, M. P. 275-276 C. (dec.) when recrystallized from methanol.

Analysis.Calcd. for C21H33N3O2.3HC]: C, H, 7.75. Found: C, 53.6; H, 7.47.

Example 3 (2 diethylaminoethylamino) 8 (3,4 methylenedioxybenzyl)nortropane bismethi0dide.A solution of 7.0 g. of 3-(2-diethylaminoethylamino) 8 (3,4 methylenedioxybenzyl)nortropane in 20 cc. of acetonitrile was treated with 6 ml. of methyl iodide. The crystalline material which separated was collected by filtration and recrystallized from methanol, giving 3.8 g. of 3-(2-diethylaminoethylamino) 8 (3,4 methylenedioxybenzyl)nortropane bismethiodide, M. P. 234-237 C.

22 Analysis.Calcd. for C H IN O N, 6.53; I, 39.45 Found: N, 6.43; I, 39.40.

Example 91 (a) 8 (4 chlorobenzyl)nortropanone was prepared from 40 g. of 2,5-diethoxytetra'hydrofuran, 50 g. of ethyl acetonedicarboxylate and 44.5 g. of 4-chlorobenzylamine hydrochloride according to the manipulative procedure described above in Example 79, part a. There was thus obtained 21 g. of 8-(4-ch'lorobenzyl)nortropanone, B. P. 168-180" C. (0.8 mm.) which Was converted to its hydrochloride salt and recrystallized from ethanol and isopropyl alcohol.

(b) 3 (2 diethylaminoethylamino) 8 (4 chlorobenzyl)nortropane EI; Y=NH, 11:2, m=1,

was prepared from 8 (4 chlorobenzyl)nortropanone (obtained by neutralization of 9.0 g. of its hydrochloride salt), 6 g. of 2 diethylaminoethylamine and 0.5 g. of

platinum oxide catalyst according to the manipulative procedure described above in Example 1.

Example 92 3 (2 diethylaminoethylamino) 8 (4 chlorobenzyl)n0rtr0pane trihydr0chl0ride.The crude 3 (2- diethylaminoethylamino) 8 (4 chlorobenzyl)nortropane obtained above in Example 91, part b, was treated with an excess of ethanolic hydrogen chloride. The crystalline product which separated (8.72 g.) was collected by filtration and recrystallized from ethanol, giving 3-(2- diethylamincethylamino) 8 (4 chlorobenzyl)nortropane trihydrochloride, M. P. 273275 C.

Analysis-Calm. for C H C1N .3HCl: C, 52.30; H, 7.68; N, 9.15. Found: C, 51.93; H, 7.96; N, 9.10.

Example 93 (a) 8 (2 chlorobenzyl)nortropanone was prepared from 40 g. of 2,5-diethoxytetrahydrofuran, 50 g. of ethyl acetonedicarboxylate and 44.5 g. of 2-chlorobenzylamine hydrochloride according to the manipulative procedure described above in Example 79, part a. The crude hydrochloride salt (29.7 g.) separated directly and was recrystallized from water, giving 8 (2 chlorobenzyDnortropanone hydrochloride, M. P. 211-213 C. (dec.).

(b) 3 (2 diethylaminoethylamino) 8 (2 chlorobenzyl)nortropane [-I; Y=NH, n=2, m=l,

was prepared from 8 (2 chlorobenzyl)nortropanone obtained from 21.4 g. of its hydrochloride salt), 11.6 g. of Z-diethylaminoethylamine and 0.6 g. of platinum oxide catalyst according to the'manipulative procedure described above in Example 1. The crude free base was converted to its trihydrochloride salt (25.1 g.) which was recrystallized from absolute ethanol.

Example 94 3 (2 diethylaminoethylamino) 8 (2 chlorobenzyhnorlropane bismethiodide.-A solution of 3 (2- diethylaminoethylamino) 8 (2 chlorobenzyDnortropane (obtained by neutralization of 9.2 g. of its hydrochloride salt) in 50 cc. of acetonitrile and 10 cc. of ethanol was treated with 6 cc. of methyl iodide. The crystalline material which separated was recrystallized from methanol, giving 3 (2 diethylaminoethylarnino)- 8 (2 chlorobenzyl)nortropane bismethiodide, M. P. 232234 C.

fQI' CzgHggCigNgI N, I, Found: N, 6.61; I, 39.7.

Example 95 (a) 8 (2 methoxybenzyl)nortropanone was prepared from 40 g. of 2,5 diethoxytetrahydrofuran, 50 g. of ethyl acetonedicarboxylate and 34.5 g. of 2 methoxybenzylamine according to the manipulative procedure described above in Example 7, part a. There was thus obtained 30.5 g. of 8-(Z-methoxybenzyl)nortropanone, B. P. 174-181 C. (0.2-0.5 mm), n =1.5O61-5. The latter was converted to its hydrochloride salt havingthe M. P.

177-178 C. (dec.). 7

(b) 3 (2 -.diethylaminoethylamino) 8 (2 methoxybenzyl)nortropane [1; Y =NH, 11:2, m=1,

R=2-CH OC H CH N=B=N(C,H,),1

was prepared from 8 (2 methoxybenzyl)nortropanone (obtained by neutralization of 19.7 got its hydrochloride salt), 11.6 g. of 2-diethylaminoethylamine and 0.7 g. of platinum oxide catalyst according to the manipulative procedure given above in Example 1.

7 Example 96 3 (2 dietlzylaminoethylamino) 8 (2 methqxyb'enzyl)nortropzme trihydrochlorideL-The crude 3 (2- diethylaminoethylamino) 8 (2'- methoxybenzyl)nortropane (obtained above in Example 95, part b) was treated with an excess of ethanolic hydrogen chloride. There I was thus obtained 15.4 'g. of "3 (2-diethylaminoethylamino) 8 (2 methoxybenzyDnortropane trihydrochloride, M. P. 248-251 C. when recrystallized from ethanol. 7 Example 97 3 (2 diethylaminoethylamino) 8 (2 methoxybenzyl)nortropane bismethiodide;-A solution of 3 (2- V V diethylam'inoethylaminm- 8 (2 rnethoXy-benzyl) ,nor-

tropane (obtained by neutralization-of 9.3 g. of its hydrochloride salt) in 50 cc. of acetonitrile was treated with 4 cc. of methyl iodide. The crystalline material which separated was collected by filtration and recrystallized from methanol, giving 4.5 g. of 3-(2-diethylaminoethylamino) 8 (2 ,-.methoxybenzyl)nortropane bismethiodide, M. P. 2185-2215 C.

Anaylsis.Calcd. for c ,-,I N,o:' N, 6.51; I, 39.3.

, Found: N, 6.52; I, 40.2. V

7 Example 98 (a) 8-phenylnortr0pano ne.-A solution was prepared from 36.2 g. of 2,5-diethoxytetrahydrofuran in 240 cc. of water containing 0.6 ml. of concentrated sulfuric acid A second solution was prepared from 97 g. of acetonedicarboxylic acid,146 g. of 'sodiumacetate trihydrate and 27 g. of aniline in 3.5 liters of water. The first'solution was warmed on a steam bath for fifteen minutes, cooled and added to the second solution; The reaction mixture was kept overnight, and the solid which separted was collected by filtration and dissolved in 1 liter of 5% hydrochloric acid at 60 C. The solution was cooled, made basic with ammonia and the product collected by filtration and recrystallized from dilute methanol, giving 11.4 g. of 8- phenylnortrop'anone, M. P. 107-109 C.. a

(b) 3 (2 diethylamiuoethylamino) 8 -phenylnortropane cording t'o the manipulativeprocedure described above in Example 11. j

. 24 Example 100 (a) 3-[Z-(I-pijreridyl)ethylimino] 9 methylgrdnatanine.A mixture of 29.8 .g. of pseudopelletierine (hy- 50 ml portions of benzene, and the total organic material concentrated and distilled. The fraction boiling at 150-200? C. (0.5-1.5 mm.) was collected and redistilled giving 27.8 g. of 3-[2-(l-piperidyD-ethylihainol- 9-methylgranatanine, B. P. 164-176 (1.0 mm),

(b) 1 [2 (l -.piperidyl)ethyl] granatanyl] 3 phenylthiourea (isomers A and B) [1;

A' solution of 27.8 g. of 3 [2 (1 -piperidyl)-ethyl-- imino] 9 methylgranatanine in 40.0.g. of 4. methyl- 2-pentanol was added over a period of two hours to a suspension of 9.2 g. of sodium powder in 200ml. of

toluene. The reaction mixture was refluxed and stirred for thirty minutes, kept overnight and then warmed .to about 90 C; while ml." of water was slowly added to destroy excess sodium.- The mixture was cooled, the. layers were separated, the aqueous layer was saturated with potassium carbonate andextracted with three.100.ml. 3

portions of toluene. The combined toluene layers were concentrated and the residue containing a mixture of isomers of 3-[2-(l-piperidyD-ethylamiholf 9 methyl To the latter solution was slowly added 15.0 g. of phenylisogranatanine was dissolved'in ml. of methanol.

thiocyanate. The solid material which formed was col- ,lected'by filtration, 34.4 g.,.M. P. 158-162 'C. afterrecrystallization from ethyl acetate. By fractional. crystallization from methanol two isomers of 1-[2-(1-piperidyl)ethyl]-1-'[3-(9-methyl)granatanyl] r 3 phenyl- .thiourea were-isolated. The more soluble isomer (isomer V A) was obtainedin the form of prisms, M. 1 .174.5-

Found: S, 8.30; N, 14.03.

176. C. after recrystallization from ethyl acetate. The more sparingly soluble isomer (isomer B) was obtained in the form of needles, M. P. 1'73-174.5?C. 'A mixture of the twojisomers showed a depression in melting point.

Analysis.(lsomer A) Calcd. for C H N S: 'S, 8.00; N, 13.95. Found:' S, 8.12; N, 14.06. (Isomer 'B) Example 101 1 3-[ (2 (1 -piperidyl) ethylamino] -9-methylgranatanine trihydrochloride (isomer A)) [I; Y -'-,NH, n=2, m=2, R=CH3, f ethyl] '1 [3-(9-methyl)granatanyl]-3-phenylthiourea (isomer A, M. P..174.5-176 C.) (7.3 g.) was dissolved in ml. of methanol containing 25 ml. of 4 N hydrogen chloride in ethanol. The solid was then removed in vacuo, the residue heated thirty minutes at 100 C., dissolvedin 50 ml. of ethanol, and the productwa s allowed to crystallize; The material was collected by filtration,

washed with 25 ml. of absolute ethanol and dried at 70 1 Example 102- 3 [2 (1 piperidyDethylamino] 9 -.methylgranataj ninetrihydrochloride (isomer B) was prepared from 9.0'

g. of 1- [2-(1-piperidyl)ethyl]-1-[3-(9-methyl)granatanyll-3-phenylthiourea (isomer B; M. P. ,173-174.5 C.)

ease-59s according to the manipulative procedure described above in Example 101. The material thus obtained was recrystallized from 4-methyl-2pentanol, giving 6.8 g. of

3 [2-(1-piperidyl)ethylaminol 9 methylgranatanine trihydrochloride (isomer B), M. P. 276 C. (dec.).

Example 103 Example 104 (a) 3 (2 diethylaminoethylimino)tropane was prepared from 69.5 g. of tropanone, 63.8 g. of Z-diethylaminoethylamine and 500 mg. of zinc chloride according to the manipulative procedure described above in Example 100, part :1. There was thus obtained 92.2 g. of 3 (Z-diethylaminoethylirnino)tropane, B. P. 117131 C. (0.6 mm.).

(b) 3 (2 diethylaminoethylamino)tropane was obtained as a mixture of isomers from 47.4 g. of 3-(2-diethylamiuoethylimino)tropane, 22.0 g. of sodium and 375 ml. of absolute ethanol according to the manipulative procedure described above in Example 100, part b.

(c) 1-(Z-d'ietlzflamitmethyl) 1 (3 pseudtr0panyl)- 3-phenylZhi0urea.- A methanol solution of 1 cc. of the mixture of isomers of 3-(Z-diethylaminoethylamino) tropane, obtained in part b above, was treated with an excess of phenylisothiocyanate. The product was fractionally crystallized from ethyl acetate, and there were obtained two compounds, M. P. l69172 C., identical with the 1-(2-diethylaminoethyl) l (3-tropanyl)-3- phenylthiourea obtained above in Example 103, and the stereoisomeric (l-(2-diethy1aminoethyl) l (3-pseudo tropanyl)-3-phenylthiourea, M. P. 138-l39.5 C.

Analysis.Calcd. for -C H N S: N, 14.96; S, 8.56. Found: N, 15.06; S, 8.38.

Example 105 3-(Z-diethylaminoethylamino)pseudotropane trihydrochloride was prepared by hydrolysis of 11.7 g. of l-(2-diethylaminoethyl) -1-(3 pseudotropanyl) -3-phenylthiourea according to the manipulative procedure described above in Example 101. The compound had the M. P. 276 C. dec.).

Analysis.Calcd. for C H NQHCI: C1, 3050; C, 48.3; H, 9.22. Found: Cl, 30.05; C, 48.0; H, 9.33.

xample 106 3-(Z-diethylaminoethylamino)pseudotropane bismethiodide.-A solution of 2.4 g. of 3-(2-diethylaminoethylamino)pseudotropane in 50 ml. of ethanol was treated with 2.0 cc. of methyl iodide. The crystalline material which separated (3.0 g.) was recrystallized from methanol, giving 3-(Z-diethylaminoethylamino)pseudotropane bismethiodide, M. P. 279281 C.

Analysis.--Caicd. for C18H35I2N3: N, 8.03; I, 48.5. Found: N, 8.09; I, 48.4.

Example 107 (a) 3-[2-( l-pyrrolidyDethylimiuo] 9 methylgranatanine was prepared from 13.8 g. of pseudopelletierine, 10.5 g. of 2-(l-pyrrolidyDethylamine and 300' mg. of zinc chloride according to the manipulative procedure described above in Example 100, part a. There was thus obtained 12.0 g. of 3-[2-(1-pyrrolidyl)ethyliminol- 9-methylgranatanine, '13. P. l44-146 C. (1.0 mm), n =1.5252.

' ('b') 3-[2-(1 pyrrolidyl)athylamino]-9-methylgranatanine [I; Y:NT-I, 12:2, m:2, R:CH N:B:NC H was prepared by catalytic hydrogenation of 3-[2-(l-pyrrolidyl)ethylimino]-9-methylgranatanine obtained above in part a in 200 ml. of ethanol with platinum oxide catalyst. There was thus obtained 8.5 g. of 3-[2-(1-pyrrolidy1)ethylaminol-9-methylgranatanine, B. P. -157 C. (2 mm.), n :1.5l02.

Example .108

1-[2-(1 pyrr0lizlyl)ezltyll-1-[3-(Q-methyDgrantIZanyIJ- 3-phenylthz'ourea.-A solution of 1.25 g. of 3-[2-(1-pyrrolidyl)ethylamino] 9 methylgranatanine in methanol was treated with 0.75 g. of phenylisothiocyanate. The product which separated was recrystallized from ethyl acetate, giving -1-[2-(1-pyrrolidyl)ethyl]-1-[3-(9 -methyl)granatanyl]-3-phenylthiourea, M. P. 173-174- C.

Analysis.Calcd. for C H N S: S, 8.29; N, 14.51. Found: 8, 8.02; N, 14.49.

Example 109 3-[2-(1 -pyrrolidyl)erhylaminol 9 methylgranatanine bismethi0dide.-A solution of 2.5 g. of 3-[2-(l-pyrrolidyl)-ethylamino-9-methylgranatanine in 10 ml. of methanol was treated with 1.2 cc. of methyl iodide. The product which separated was recrystallized from methanol, giving 1.3 g. of 3-[2-(1-pyrrolidyl)ethylamino]-9-methylgranatanine bismethiodide, M. P. 278 C. (dec.).

Analysis.Calcd. for C H I N I, 47.4; N, 7.85. Found: 1, 47.0; N, 7.89.

Example 1 10 ml. of ethanol in the presence of 0.5 g. of platinum oxide catalyst.

The product (8.4 g.) boiling at -116122 C. (0.2 mm.) was collected and redistilled, giving 3-(2-diethylaminoethylamino)9-methylgranatanine, B. P. 128- 130 C. (0.6 .mm.), n :1.4920.

Example 111 1-(Z-diethylaminoethyl) 1 (9 methylgrmzatanyl) -3- phenylthiourea (isomer B) [l; Y:N(CSNHC H 11:2, m:2, R:CH N:B:N(C H ].A solution of 0.6 g. of 3- (Z-diethylarninoethylamino)-9-methylgranatanine, obtained inExarnple 110, part b above, in 2 cc. of methanol was treated with 0.32 g. of phenylisothiocyanate. The product which separated was recrystallized from ethyl acetate, giving 1-(2-diethylaminoethyl)-l-(9-rneth -ylgranatanyl)-3-phenylthiourea (isomer B), M. P. 188

Analysis.-Calcd. for C H N S: S, 8.25; N, 14.42.

Found: S, 8.22; N, 14.49.

Example 1 12 (a) 3.-(Z-diethylaminoethylamino)-9-methylgranatanine (mixture of isomers) was prepared by reduction of 20.5 g. of 3-(Z-diethylaminoethylirnino)-9-rnethylgranatanine (Example 110, part a) with 7.5 g. of sodium and 32.8 g. of 4-methyl-2-pentanol according to the manipulative procedure described above in Example 100, part b.

(b) 1-(2 diethylwninoethyl) -J-(9-methylgranu'tanyl)- S-phenylthioztrea (isomers A and B).A solution of the 7N, 14.42. Found: s,

.aeeewae .mixture. of isomers of 3-(2-diethylaminoethylamino) 9- methylgranatanine, obtained in part a above, in ;100 ml.

.of methanol was treated with.17.5 g. of phenylisothioi 7 Example 113 v 3-(2-diethylaminoethylarnino)-9-methylgranatanine trihydrochloride (isomer A) was prepared by hydrolysis of .10.2 g. of 1 (2-diethylaminoethyl)-1-(9-methylgranatanyl)-3-phenylthiourea (isomer A) with 15 ml. of alcoholic hydrogen chloride in 100 ml. of methanol. The product which separated was recrystallized from an ether-ethanol mixture, giving 3-(Z-diethylaminoethylamino)-9-methyl granatanine trihydrochloride (isomer A), M. P. 270 C.

. (dec.).

Analysis.Calcd. for C H N .3HCl: Cl, 29.3; C,

-49..65; H, 9.45. Found: Cl, 29.2; C, 49.87; H, 9.54.

Example 114 '3- (2-diethylaminoethylamin0) -9methylgranatanine trihydrochloride (isomer B).-When I-(Z-diethylaminoeth- I yl) 1-(9-methylgranatanyl) -3 -phenylthiourea (isomer B) M. P. 189191 C., was dissolved in ethanol; and alcoholic hydrogen chloride was added, the dihydrochloride,

M. P. 205 C. (dec.) of the thiourea derivative precipitated; The latter (6.0 g.) was dissolved in 50 ml. 'of

methanol and-treated with 3 cc. of 8N ethanolic hy-. drogen chloride. After standing for sixteen days, 'the methanol solution was concentrated to a 10 ml. volume, and ml. of ethanol and 15 ml.jof dry benzene were added. There separated from solution 2.5 g. of 3-(2-diethylaminoethylamino) 9 methylgranatanine trihydro- V chloride (isomer B), M. P. 185 C. (dec.).

7 Example 115 V 3-(Z-diethylaminoethylamino) 9 methylgranatanine bismethiodide (isomer A).A solution of 3-(2rd16l'hYlaminoethylamino)-9-methylgranatanine (isomer A) (obtained by neutralization of 2.6 g. of the trihydrochloride 7 .salt) in 10 ml. of methanol was treatedwith 1.2 cc. of

' methyl iodide.

'was recrystallized from methanol, giving 3-(2-dicthyl- The product which separated (2.3 g.)

aminoethylamino)-9-methylgranatanine V bisme'thiodide (isomer A), M. P. 277279 C. (dec.).

Analysis.-Calcd. for C17H37I2N3: I, 47.2; N, 7.82.

Found: I, 47.3; N, 7.88.

Example 116 I-(Z-diethylaminoethyl) 1 3 [8-(2-chlorobenzyl)] nortropanyl-3-phenylthiourea [1; 'Y=N( CSNHC H 71 772 1, R=2=ClC H CH was prepared from 3-(2-diethylaminoethylamino)-8-(2-chlorobenzy1)nortropane (prepared by neutralization of 4.0 g.

of the trihydrochloride salt, see Example 93) and 1.2 cc. of phenylisothiocyanate in 40 ml. of ethanol. The product which'separated was recrystallized fiom ethanol, giving 3.4 g. of l-(2-diethylaminoethyl)-1-3-[8-(2-chlorobenzyl) lnortropanyl-3-phenylthiourea, M. P. 124-126 C. 'Analysis..'Calcd. for C27H3'1CIN4S: S, 6.61; N 8.66. Found: S, 6.61; N 8.70. a V

Example 1 1 1 (2 -diethylaminoethyl) -1-(3-tr0panyl) 3-allylthiouiea [1; Y=N(CSNHCH CH'=CH n=2, m=1, R=CH N=.B=N(C H ].--A solution of 4.0 g. of 3-(2-diethyl- .aminoethylamino) tropane in petroleum ether (Skellysolve -thiocyanatein petroleum'ether (Skellysolve B).

Found: 5, 7.21; NAP,

3- Z-diethylamirroethylamino) -8-benzylnortropane 5B) was treated with 1.7 cc. of allylisothiocyanate-. 1 The product which separated was recrystallized from petroleum ether,*giving 3.6 g. of 1-(2-diethylaminoethyl1-1- (3 tropanyl)-3-allylthiourea, M. P. 97-100 C.

Analysis.-Calcd. for C H N S: S, 9.47;'.N 8.27. Found: 8, 9.04; N 8.24. 7

Example 118 N=B=N(C H was prepared from 4.0 .g;.of-3-(2- diethylaminoethylamino)tropane.and 1.5.cc. of ethyliso- The product which separated was recrystallized from petroleum ether. giving 4.0 g. of 1-(2-diethylaminoethyl)v1- (3 -tropanyl)-3-ethylthiourea, M. P. 122.124 C Analysis.Calcd. for C H N S: S, 9.82; N, 12.87.

Found: S, 9.67; N 12.80.

Example 119 1-(2-diethylaminoethyl) 1 (3-tropanyl)-3-(4-ethoxyphenyl)'-thiourea II; Y=N(CSNHC H;OC H -4), n=2,

4.0 g. of 3-(Z-diethylaminoethylamino)tropane and 3.1

.g. of. p-ethoxyphenylisothiocyanate in 50 ml. of petroleum ether (Skellysolve B). The reaction mixture was refluxed for five minute s, cooled, and the productj which separated was recrystallized from ethanol, giving 6.0 g.

1-(2-diethylaminoethyl)-1-(3-tropanyl)-3-(4-ethoxyphenyl)-thiourea, M. P. 16.0-161 C. f

Analysis.-Calcd, for C H N OS: S,'7.66;-N 10.41.

V 7 Example 120 1-(2-diethylaminoethyl)-1-[3-(8 benzyl)'nortropanyl l R=C H CH N=B=N(C H was prepared from btained by neutralization of 4.0 g. of its trihydrochloride) '(see Example 80) and 1.3 cc. of phenylisothiocyanate in 40 cc. of ethanol. The product which separated was recrystallized from ethanol, giving l-(2-diethylaminoethyl)-1-[3-(8-benzyl)nortropanyll 3 phenylthiourea,

Analysis.Calcd.; for C H N S: S, 7.11; N 9.33.

Found: S, 7.16; N 9.33. r

Example 121 1 1-(2-diethylaminoethyl)-1-{3-[8 (3,4 methylenedioxybenzyl)l nortropanyl} 3 phenylthiourea [1;

was prepared from 3-(2-diethylaminoethylamino)-8-(3,4- methylenedioxybenzyl)nortropane (obtained by neutralization of 4.0 g. of its trihydrochloride salt, see Example 89) and 1.2 cc. of phenylisothiocyanat'c. The product which separated was recrystallized from ethanol, giving 1-(Z-diethylaminoethyl)-1-{3-[8 (3,4 methylenedioxybenzyl)]-nortropanyl}-3-phenylthiourea, M. P. 148-149'' Analysis.Calcd. for C H N O S: S, 6.33; N 8.30. Found: S. 5.97; N 8.57. I

Example 122 V 3 [(2 diethylaminoethyl)acetylamino]tropane II;

N=B=N(C H A mixture of 22 g. of 3-(2-diethylaminoethylamino)tropane and 30 cc. of acetic anhydride was heated on a steam bath for two hours, kept for. two

'days at room temperature, poured into ice-water, and the solution made basic and extracted. 'The extracts were concentrated and the residue distilled. The' fraction 75 boiling at 143 c. 0.05-0.15 mm.) (20.1 g.) was period of twenty minutes.

collected and redistilled,.giv ing 3-[(2-diethylaminoethyl) acetylam'inoltropane, B. P. 142-144 C. (0.09 mm.), 11 :1.4980. v A sample of the latter was converted to the picrate which was recrystallized from ethanol and had the M. P. 198-200" C.

Example 123 Example 124 3- (Z-diethylaminoethyl)ethylamino] tropane bismethi- 0dide.A solution of 0.47 g. of 3-[(2-diethylaminoethyl)ethylamino]tropane in cc. of acetonitrile was treated with 0.5 cc. of methyl iodide. There was thus Obtained 0.63 g. noltropane bismethiodide, M. P. 230231 C. (dec.).

Analysis.-Ca1cd. for C13H39I2N3: I, 46.0; N, 7.63. Found: I, 45.4; N, 7.74.

Example 125 3 [(2 diethylaminoethyl) ethylamino] tropane bisethiodide.A solution of 2.0 g. of 3-[(2diethylaminoethyl)- ethylamino]tropane in ml. of acetonitrile was treated with 2.0 cc. of ethyl iodide. There was thus obtained 3.6 g. of 3- (2--diethylaminoethyl)ethylamino] tropane bisethiodide, M. P. 226 c. (dec.).

Analysis.-Calcd. for C H I N I, 43.8; N, 7.25. Found: 1, 43.7; N, 7.46.

Example 126 3 [(2 diethylaminoethyl) propionylamino1tr0pane [1;

Y:N(COCH CH 11:2, m: 1, R=CH 3-(2-diethylaminoethylamino)tropane (48 g.) was cooled to the temperature of solid carbon dioxide, 50 cc. of propionic' anhydride was added and the mixture was allowed to warm to 70 C. The reaction mixture was worked up as described above in Example 122, giving 45.8 g. of 3-[(2-diethylarninoethyl)propionylamino]tropane, B. P. 160 C. (0.5 mm.), 12 :1.49405. A sample was converted to the picrate, M. P. 173--176 C. when recrystallized from aqueous dimethylformamide.

Example 27 3 [(2 diethylaminoethyl)propylamino1tropane [I; Y=N(C H 11:2, m:1, R CH N=B=N(C H A solution of 29.5 g. of 3-[(Z-diethylaminoethyDpropionylamino]tropane in 100 cc. of ether was added to a suspension of 4.0 g. of lithium aluminum hydride in 100 m1. of dry ether at such a rate to maintain gentle reflux. The reaction mixture was stirred for one hour, 15 ml. of ethanol and ml. of 20% sodium potassium tartrate solution were added, and the mixture was stirred for one and one-half hours. The mixture was filtered and the filtrate dried over potassium carbonate, concentrated, and the residue distilled, giving 23.6 g. of 3-[(2- diethylaminoethyl)propylamino]tropane, B. P. 119-126 C. (0.1 mm.), 12 :1.4835. A sample of the latter was converted to the picrate which had the M. P. 223 C. (dec.) when recrystallized first from aqueous dimethylformamide and then from a dimethylformamide-ethanol mixture.

Example 128 3 [(2 diethylaminoethyl)propylamino]tropane bisof 3- Z-diethylaminoethyl) ethylaniimethiodide..A solution of 2.0 g. of 3-[(2-diethylaminoethyl)propylamino]tropanc in 30 cc. of acetonitrile was treated with 2 ml. of methyl iodide. There was thus obtained 2.0 g. of 3-[(Z-diethylaminoethyl)propylamino]- tropane bismethiodide, M. P. 203-209 C. (dec.).

Analysis.-Calcd. for C19H41I2N3i Found: 1, 44.5; N, 7.46.

Example 129 3 [(2 diethylaminoethyl)butyrylamino1tropane [1; Y=N(COCH CH CH 11:2, m:1, R=CH was prepared from 48 g. of 3(2-diethylaminoethylamino)tropane and 50 cc. of butyric anhydride according to the manipulative procedure described above in Example 126. There was thus obtained 50.5 g. of 3-[(2- diethylaminoethyl)butyrylaminojltropane, B. P. 162166 C. (0.7 mm.), n :1.4935. A sample of the latter was converted to the picrate which had the M. P. 194-196 C. when recrystallized from aqueous dimethylforrnamide.

Example 130 3 [(2 diethylaminoethyl)butylarnino]tropane [1; Y:N(C4H9), 71 2, m l, Ii CH3, was prepared from 30.9 g. of 3-[(2-diethylaminoethyl)- butyrylamino]tropane and 4.0 g. of lithium aluminum hydride according to the manipulative procedure described above in Example 127. There was thus obtained 25.4 g. of 3-[(Z-diethylaminoethyl)butylamino]tropane, B. P. -430" C. (0.1 mm.), 1z =1.4839. A sample of the latter was converted to the picrate which had the M. P. 208210 C. (dec.) when recrystallized from a dimethylformamide-ethanol mixture.

Example 131 3 {[2 (1 pyrrolidyl) ethyl] formylaminohropane [1; Y=N(COH, n:2, 111:1, R CE-l N B=NC H ].A mixture of 15.5 g. of 3-[2-(l-pyrrolidyl)ethy1amino]- tropane and 10 cc. of formic acid was heated on a steam bath for about fifteen hours. The reaction mixture was poured into ice-water, made basic with 35% sodium hydroxide solution and extracted with benzene. The benzene solution was concentrated and the residue distilled. The fraction boiling at 133154 C. (0.1 mm.) was collected and redistilled, giving a 3-{[2-(l-pyrro1idyl)- ethyl]formylamino}tropane, B. P. l66-172 C. (0.9 mm.), n :1.5131. A sample of the latter was converted to the picrate which had the M. P. 192-194 C. when recrystallized from aqueous dimethylformamide.

Example 132 l (2 diethylaminoethyl) 1 [3 (8 phenyDnortropanyl]-3-phenylthiourea [1; Y=N(CSNHC H 11:2, 111:1, R=C H N=B=N(C l-l was prepared from 3-(2-diethylaminoethylamino)-8-pheuylnortropane (Example 98) and phenylisothiocyanate in methanol solution. The product which separated was recrystallized from ethanol, giving 1-(2-diethylaminoethyl)-1-[3-(8- phenyl)nortropanyl]-3-phenylthiourea, M. P. 16l163 C.

Example '133 3 [(2 diethylaminoethyl)acetylamino] 8 phenylnortropane [1; Y N(COCH 11:2, 112:1, R C H N=B:N(C ZI was prepared from 15 g. of 3-(2-diethylaminoethylamino)-8-phenylnortropane (Example 98) and 20 ml. of acetic anhydride according to the manipulative procedure described above in Example 122. There was thus obtained 11.5 g. of 3-[(2-diethylaminoethyl)- acetylamino]-8-phenylnortropane, B. P. 183-198 C. (0.2 mm.), 12 =1.5470.

Example 134 3 [(2 diethylaminoethyl)ethylamino] 8 phenylnortropane [1; Y=N(C H 11:2, 111:1, R=C H diethylaminoethyl) acetylamino] S-phenylnortropane and 4 g. of lithium aluminum hydride according to the manipulative procedure described above in Example 127. There-was thus obtained 6 g. of 3:[(2-diethylaminoethyl)- ethylamino]-8-phenylnortropane, B. P. ISO-184 C. (0.9 mm.), l'l =1.5370. V i i V This application is a continuation-in-part of my copending application, Serial No. 380,884, filed September 17, 1953, now abandoned. j

Iclaim: 1. A cycloalkane having a 15.-imino bridge and haying a hydrocarbon radical attached to the imino nitrogen and a tertiary-amino-lower-alkylene group attached through an atom of an element from the group consisting of oxygen and sulfur to the cycloalkane carbon atom in the 3-position, wherein the cycloalkane isa member of the group consisting of'cycloheptane and cyclooctane,

and the tertiary-amino radicalisa member of the' group consisting ofdi-loWer-alkylamino, l-piperidyl, 1-pyrroli- 4-morpholinyl, and monocarbocyclic' aryl-loweralkylamino radicals, the monocarbocyclic aryl moiety in the last named radical being selected from the group consisting of ,phenyl and'ph enyl substituted by from one to three substituents selected. from the group consisting of lower-alkyl, lower-alkoxy and halogen radicals.

anion which does not substantially increase the toxicity of the compound as a whole to animal organisms.

3. A quaternary ammonium salt of an amine having the formula (CH2)m-CHCH N-R CHY'C,.Hz,.-N=B' CHrCH- -CH1 7, wherein Y is O, n is an integer from 2 to 6, m is 1, N =B is a l-piperidyl radical, R is a loweralkyl group, and the radicals N=B' and Y are attached to diiferent carbon atoms of C H said salt having an anion which does not substantially increase the toxicity of the compound as a whole to animal organisms.

4. A quaternary ammonium salt of an amine having the formula (CH2)m-CH-CH: A

fit-R HY' 0 n112,.N=13' CHzCH H2 7 wherein Y is O, n is an integer from 2 to 6, m is 1, N=B is a l-pyrrolidyl radical, R is a lower-alkyl group, and

' substituted tropane having the formula the radicals -N=B' and Y are attached to different carethoxy)tropane, said salt having an anion which does.

not substantially increase the toxicity of the 'compoun as a whole to animal organisms.

6. 'A quaternary ammonium salt of 3-(2-diethylamino- 8. A quaternary ammonium salt of 3-[2-(1-pyrrolidyl) ethoxy]tropane, said salt having an 7 substantially increase the toxicity of the compound as a wholeto animal organisms.

9. Aquaternary ammonium salt 'of tertiary-aminosubstituted tropane having the formula aurora-+011; r

Ni-CHa HY'o..H,.N=Bt

on,- H H2 1 wherein Y is O, C H is an alkylene radical of 26 carbon atoms, N =B isa di-lower alkylamino radical,

and the radicals N B" and Y are attached to different carbon atoms of C H said salt having an anion which does not substantially increase the toxicity of the com pound as a whole to animal organisms.

10. A quaternary ammonium salt of a tertiary-amin wherein Y isO, C,,H is an alkylene radical of 2-6 carbon atoms, N==B' is a l-piperidyl radical, and the radicals N=B' and Y are attached to difierent carbon atoms of C Zn: said salt having an anion which does :not substantiallyincrease the toxicity .of the compound as a whole to animal organisms.

11. A quaternary ammonium salt of a tertiary-aminosubstituted tropane having the formula wherein Y" is O, C H is an alkylene radical of 2-6 carbon atoms, N=B' is a 1pyrrolidyl radical, and the radicals N=B' and Y are attached to different carbon atoms of C l-I said salt having an anion which does not substantially increase, the toxicity of the compound.

as a whole to animal organisms. V

12. 3 (2 dimethylamihoethoxyfiropane bismethohalide. v 13. 3-(2-diethylaminoethoxy)tropane bismethohalide. 14; 3 [2 (1 pyrrolidyl)ethoxy]tr0pane'bismetho halide. j

15. The process for preparing a cycloalkane having a :.1,5-imino bridge and having a hydrocarbon radical attached to the imino nitrogen and a tertiary-amino-loweralkylene group attached through an element from the group consisting of oxygen-and sulfur to the cycloalkane ,carbon atom in the 3-position, wherein the cycloalkane is .a member of the group consisting ofcycloheptane and cyclooctane, and the tertiary-amino radical is a member of the group consisting of di-lower-alkylaminofl mercaptide having a hydrocarbon radical attached to the.

imino nitrogen with a tertiary-amino lower alkyl halide,

the cycloalkyl and tertiary-amino radicals having the meanings given above.

16. The process for preparing a quaternary ammonium.

salt of a tertiary-amino-substituted tropane having the formula 7 om-hn-on,

I!ICH: .CH Y 'CnH2-N=B H,- H H;

wherein Y 'is'O, C Hg is an alkyl ene radical of 2-6 anion which does not i i asaaees carbon atoms, N=B' is a di-lower-alkylamino radical, and the radicals N=B and Y are attached to different carbon atoms of C I-I which comprises reacting an alkali metal derivative of tropine with a di-lower-alkylaminoloWer-alkyl halide, and reacting the resulting amine with a compound of the formula RX" wherein R is a hydrocarbon radical and X is the anion of a strong acid, which anion does not substantially increase the toxicity of the compound as a whole to animal organisms.

17. The process for preparing a quaternary ammonium salt of a tertiary-amino-substituted tropane having the formula CHrCH-CH:

OH:- H H:

wherein Y is O, C H is an alkylene radical of 2-6 carbon atoms, N:B' is a l-piperidyl radical, and the radicals N=B and Y are attached to different carbon atoms of C Hg which comprises reacting an alkali metal derivative of tropine with a (1-piperidyl)-lower-alkyl halide, and reacting the resulting amine with a compound of the formula R'X" wherein R is a hydrocarbon radical and X" is the anion of a strong acid, which anion does not substantially increase the toxicity of the compound as a whole to animal organisms.

18. The process for preparing a quaternary ammonium salt of a tertiary-amino-substituted tropane having the formula wherein Y is O, C I-I is an alkylene radical of 2-6 carbon atoms, N=B' is a 1-pyrrolidyl radical, and the radicals N=B and Y are attached to different carbon atoms of C t-i which comprises reacting an alkali metal derivative of tropine with a (l-pyrrolidyl)-lower-a1kyl halide, and reacting the resulting amine with a compound of the formula RX" wherein R is a hydrocarbon radical and X is the anion of a strong acid, which anion does not substantially increase the toxicity of the compound as a whole to animal organisms.

19. The process for preparing 3-(2-dimethylarninoethoxy)tropane which comprises reacting an alkali metal derivative of tropine with a Z-dimethylaminoethyl halide.

20. The process for preparing 3-(2-diethylarninoethoxy)tropane which comprises reacting an alkali metal derivative of tropine with a Z-diethylaminoethyl halide.

21. The process for preparing 3-[2-(1-pyrrolidyl)- ethoxy] tropane which comprises reacting an alkali metal derivative of tropine with a 2-(1-pyrrolidyl)ethyl halide.

22. 3-(2-dimethylaminoethoxy)tropane bisethohalide.

23. 3- [2-( 1piperidyl) ethoxy] tropane bismethohalide.

24. 3- [3-( l-piperidyl) propoxy] tropane bismethohalide.

25. 3-(Z-diethylaminoethoxy)pseudotropane bismethohalide.

26. 3-(S-diethylaminopropoxy)tropane bismethohalide.

OTHER REFERENCES Anderson et al.: Chem. Abstracts, vol. 47, col. 11203 (1953) (abstract of article dated 1952).

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,836,598 May 27, 1958 Sydney Archer It is hereby certified that error appears in the printed specification of the above numbered patent requirlng correction and that the said Letters Patent should read as corrected below.

Column 7, line 7 5, for 3-[ (diethylaminoread 3-[(2-diethylamino column 8, lines 4 to 6 inclusive, should read as follows instead of as in the patent: recrystallized from methanol, giving 3-[(2-diethylaminoethyl)- amino]tropane bismethobromide, M. P. 289290 O. (dec.).; line 21, for 3-[-diethylaminoread 3-[(2-diethy1amino-; column 14, line 58, for N=B=CH read N=B'=N(CH column 15, line 6, for C H N O2CHlO read C H N O.2HClO line 15, for hour hours read four hours; column 22, line 16, for N =B= (C H read 11118 69, f0! C22H33C12N3 read O22H3301I2N3' column 27, line 5, for aceate read acetate; line 23, for 270 C. read 278 C.-; line 60, for read n=2,; same line, for

column 29, line 10, for 1.03 g. read -10.3 g.; column 30, line 7, for N, 7A6 read N, 7.56.

Signed and sealed this 19th day of August 1958.

Attest: KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Ofioer. Uomnz'ssz'oner of Patents. 

1. A CYCLOALKANE HAVING A 1,5-IMINO BRIDGE AND HAVING A HYDROCARBON RADICAL ATTACHED TO THE IMINO NITROGEN AND A TERTIARY-AMINO-LOWER-ALKYLENE GROUP ATTACHED THROUGH AN ATOM OF AN ELEMENT FROM THE GROUP CONSISTING OF OXYGEN AND SULFUR TO THE CYCLOALKANE CARBON ATOM IN THE 3-POSITION, WHEREIN THE CYCLOALKANE IS A MEMBER OF THE GROUP CONSISTING OF CYCLOHEPTANE AND CYCLOOCTANE, AND THE TERTIARY-AMINO RADICAL IS A MEMBER OF THE GROUP CONSISTING OF DI-LOWER-ALKYLAMINO, 1-PIPERIDYL, 1-PYRROLIDYL, 4-MORPHOLINYL, AND MONOCARBOXYCLIC ARYL-LOWERALKYLAMINO RADICALS, THE MONOCARBOCYLIC ARYL MOIETY IN THE LAST NAMED RADICAL BEING SELECTED FROM THE GROUP CONSISTING OF PHENYL AND PHENYL SUBSTITUTED BY FROM ONE TO THREE SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF LOWER-ALKYL, LOWER-ALKOXY AND HALOGEN RADICALS. 